3.4.23.16: HIV-1 retropepsin
This is an abbreviated version!
For detailed information about HIV-1 retropepsin, go to the full flat file.
Word Map on EC 3.4.23.16
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3.4.23.16
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antiretroviral
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ritonavir
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transcriptase
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saquinavir
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indinavir
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integrase
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cross-resistance
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isostere
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nonpeptidic
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zidovudine
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virus-1
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tipranavir
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cyp3a4
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nnrti
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drug-drug
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autoprocessing
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pharmacology
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drug development
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medicine
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hiv-rna
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lipoatrophy
- 3.4.23.16
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antiretroviral
- ritonavir
- transcriptase
- saquinavir
- indinavir
- nelfinavir
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hiv-infected
- lopinavir
- polyproteins
- flap
- darunavir
- amprenavir
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drug-resistant
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anti-hiv
- atazanavir
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virological
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haart
- gag-pol
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peptidomimetic
- virion
- p-glycoprotein
- lipodystrophy
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non-nucleoside
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integrase
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cross-resistance
- isostere
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nonpeptidic
- zidovudine
- nevirapine
- virus-1
- tipranavir
- cyp3a4
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nnrti
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drug-drug
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treatment-experienced
- lamivudine
- didanosine
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ritonavir-boosted
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autoprocessing
- efavirenz
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protease-inhibitor
- stavudine
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treatment-naive
- analysis
- raltegravir
- zalcitabine
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plasmepsins
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antiretroviral-naive
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pi-based
- pharmacology
- drug development
- medicine
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hiv-rna
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lipoatrophy
Reaction
specific for a P1 residue that is hydrophobic, and P1' variable, but often Pro =
Synonyms
CRF01_AE protease, Gag protease, HIV aspartyl protease, HIV PR, HIV protease, HIV-1 aspartyl protease, HIV-1 PR, HIV-1 protease, HIV-1 proteinase, HIV-1PR, HIV-2 protease, HIVPR, human immunodeficiency virus 1 protease, human immunodeficiency virus 1 retropepsin, human immunodeficiency virus protease, human immunodeficiency virus type 1 protease, human immunodeficiency virus type I protease, More, PR, PR1, PR2, retropepsin, retroproteinase
ECTree
3.4.23.16 HIV-1 retropepsinAdvanced search results
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Engineering on EC 3.4.23.16 - HIV-1 retropepsin
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PROTEIN VARIANTS 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
A28S
A71T
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in untreated patients, mutations L10V, K20R, and M36I are more frequent in subtype F1, while L63P, A71T, and V77I are more prevalent in subtype B
A71V
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site-directed mutagenesis of wild-type V6 enzyme, non-active-site mutation, inhibitor binding structure analysis
A71V/V82T/I84V
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site-directed mutagenesis, the mutant enzyme shows altered interactions with inhibitors compared to the wild-type enzyme
C67A
C67A/C95A
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urea denaturation is unchanged from that of the wild-type enzyme. Kcat/Km ratio for KARV-Nle-Phe(NO2)-EA-Nle-NH2 as substrate is similar to that of the wild-type enzyme
D25N
D29N
the mutation can largely reduce the binding capability of the two peptides ARVLAEAM and NLAFPQGE as compared to the wild type enzyme
D30N
D30N/L63P/N88D
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mutations in drug-resistant clinical isolates
D30N/L90M
D30N/N88D
F53L
G48H
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with VSQNYPIVQ the turnover-number of the mutant enzyme is 60% of that of the wild-type enzyme, with VSQNYPIVQ the KM-value of the mutant enzyme is 2.2fold higher than the Km-value of the wild-type enzyme
G48V
G48V/L90M
G73S
G86A
the mutant exhibits about 6000fold lower catalytic activity than the wild type enzyme
I47AV
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the mutation is associated with decreased susceptibility to protease inhibitors atazanavir and lopinavir
I47V
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the mutation is associated with decreased susceptibility to protease inhibitors darunavir and tipranavir
I50V
I54AMV
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the mutation is associated with decreased susceptibility to protease inhibitor tipranavir
I54LM
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the mutation is associated with decreased susceptibility to protease inhibitor atazanavir and darunavir
I54LMV
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the mutation is associated with decreased susceptibility to protease inhibitor lopinavir
I54M
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mutation in flap region. Activity comparable to wild-type
I54TV
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the mutation is associated with decreased susceptibility to protease inhibitor saquinavir
I54V
I54V/I84V
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site-directed mutagenesis of wild-type V6 enzyme, non-active-site mutation, the mutation leads to resistance against ritonavir, inhibitor binding structure analysis
I54V/V82A/L90M
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confer strong resistence to ritonavir, but not to amprenavir
I84AV
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the mutation is associated with decreased susceptibility to protease inhibitor atazanavir, saquinavir, indinavir, lopinavir and nelfinavir
I84V
K20M
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in treated patients, K20M, D30N, G73S, I84V, and L90M, are more prevalent in subtype B, and K20T and N88S are more prevalent in subtype F1
K20R
K20T
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in treated patients, K20M, D30N, G73S, I84V, and L90M, are more prevalent in subtype B, and K20T and N88S are more prevalent in subtype F1
K43T
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the mutation is associated with decreased susceptibility to protease inhibitor tipranavir
K45I
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mutant with significantly increased stability with half-maximal activity at 3.3 mM urea compared to 1.8 M urea for the wild-type enzyme. The kcat/Km ratio for the substrate KARVLAEAMS is 106% of that for the autoproteolysis resistant variant Q7K/L33I/L63I/C67A/C95A
L10F
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the mutation is associated with decreased susceptibility to protease inhibitors atazanavir, lopinavir and indinavir
L10FI
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the mutation is associated with decreased susceptibility to protease inhibitor nelfinavir
L10I
the mutant enzyme is resistant against inhibition by darunavir and tipranavir
L10I/G48V/I54V/L63P/V82A
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mutations in drug-resistant clinical isolates
L10I/K45R/I54V/L63P/A71V/V82T/L90M/I93L
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dimerization study on mutant protease PRMDR derived from an HIV-1-infected patient on antiviral therapy. PRMDR contains eight drug-resistant related mutations that often arise in patients on antiviral therapy, none of these mutations reside in the N- or C-terminal regions that make up the dimerization interface. PRMDR is highly resistant to autoproteolysis. Incubation with dimerization inhibitors such as peptide P27 leads to dose- and time-dependent formation of protease monomers, while incubation with a active-site inhibitor does not change the elution profile of the protease. The monomeric protease induced by P27 has fluorescent characteristics consistent with unfolded protein
L10I/L63P/A71V/G73S/I84V/L90M
L10V
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in untreated patients, mutations L10V, K20R, and M36I are more frequent in subtype F1, while L63P, A71T, and V77I are more prevalent in subtype B
L24I
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the mutation is associated with decreased susceptibility to protease inhibitors lopinavir and indinavir
L24I/M46I/F53L/L63P/V77I/V82A
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associated with resistance to saquinavir, nelfinavir, ritonavir and TL3
L33F
L63P
L76M
site-directed mutagenesis, mutant enzyme structure modelling
L76V
L89V
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the mutation is associated with decreased susceptibility to protease inhibitor darunavir
L90M
M36I
M46I
M46I/I54V/I84V
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site-directed mutagenesis of wild-type V6 enzyme, non-active-site mutation, the mutation leads to resistance against ritonavir, inhibitor binding structure analysis
M46I/I84V
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site-directed mutagenesis of wild-type V6 enzyme, non-active-site mutation, the mutation leads to resistance against ritonavir, inhibitor binding structure analysis
M46IL
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the mutation is associated with decreased susceptibility to protease inhibitors atazanavir, nelfinavir, indinavir and lopinavir
M46L
N25D
the mutation completely eliminates the binding capability of the two peptides ARVLAEAM and NLAFPQGE as compared to the wild type enzyme
N83D
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the mutation is associated with decreased susceptibility to protease inhibitor tipranavir
N88D
N88D/L90M
N88DS
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the mutation is associated with decreased susceptibility to protease inhibitor nelfinavir
N88S
PRS17
the highly drug-resistant mutant enzyme shows enhanced binding to substrate analogues RVLrFEANle and Ace-TINlerNleQR
PRV82A
the highly drug-resistant mutant enzyme shows enhanced binding to substrate analogues RVLrFEANle and Ace-TINlerNleQR
Q7
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mutant enzyme has markedly enhanced stability over the wild-type enzyme
Q7K/D29N/L33I/L63I/C67A/C95A
920fold less active than with Q7K/L33I/L63I/C67A/C95A, poor catalytic activity arises both from the destabilization of the dimer as well as changes in the active site environment
Q7K/D30N/L33I/L63I/C67A/L90M/C95A
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mutant with restricted autoproteolysis, mutation D30N alters activity observed with peptide substrates
Q7K/L331I/L631I
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mutant enzyme is highly resistant to autolysis, while retaining the physical properties, specificity, and susceptibility to inhibition of the wild-type enzyme
Q7K/L33I/K45I/L63I/C67A/N88D/C95A
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mutant with restricted autoproteolysis, mutation N88D induces small structural changes, water molecules that mediate interactions between Asn88 and Thr74/Thr31/Asp30 in other complexes are missing in N88D
Q7K/L33I/L63I/C67A/C95A
Q7K/L33I/L63I/C67A/I84A/C95A
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site-directed mutagenesis, mutations Q7K, L33I, and L63I minimizes enzyme autoproteolysis, mutations C67A and C95A prevent cysteine thiol oxidation, the I84A mutation confers drug-resistance
Q7K/L33I/L63I/C67A/R87K/C95A
4600fold less active than with Q7K/L33I/L63I/C67A/C95A
Q7K/L33I/L63I/C67A/V82A/C95A
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site-directed mutagenesis, mutations Q7K, L33I, and L63I minimizes enzyme autoproteolysis, mutations C67A and C95A prevent cysteine thiol oxidation, the V823A mutation confers drug-resistance
Q7K/T26A/L33I/K45I/L63I/C67A/C95A
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mutant with restricted autoproteolysis, mutation K45I reduces the mobility of the flap and the peptide inhibitor and contributes to an enhancement in structural stability and activity
Q7K/T26A/L33I/L63I/C67A/C95A
mutant enzyme with restricted autoproteolysis, mutation T26A destabilizes the dimer, exhibits a monomer fold and is prone to aggregation
Q7K/T26A/L33I/L63I/C67A/L90M/C95A
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mutant with restricted autoproteolysis, mutation L90M decreases dimer stability and activity, alteration of the van der Waals interactions in the hydrophobic interior at the dimer interface near the catalytic aspartates
R10K
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altered substrate specificity and catalytic rate compared to wild-type enzyme
R87K
loss of specific interactions involving the side chain of Arg87 destabilizes the mutant enzyme by perturbing the inner C-terminal region that is sandwiched between the two beta-strands formed by the N-terminal residues in the mature protease
R8K
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significant difference in subsite selection compared to wild-type enzyme
R8Q
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half maximal activity at 1.3 M urea compared to 1.8 M for the wild-type enzyme. The kcat/Km ratio for the substrate KARVLAEAMS is 15% of that for the autoproteolysis resistant variant Q7K/L33I/L63I/C67A/C95A
T26A
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mutation increases the stability of the monomer fold, mutant still exhibits a high Kd value of more than 0.5 mM
T74P
-
the mutation is associated with decreased susceptibility to protease inhibitors darunavir and tipranavir
V32I
V32I/I47V/V82I
V32T
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mutant exhibits wild-type preference for large hydrophobic residues, especially Phe, in the P1' substrate position
V77I
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in untreated patients, mutations L10V, K20R, and M36I are more frequent in subtype F1, while L63P, A71T, and V77I are more prevalent in subtype B
V82A
V82A/L90M
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confer strong resistence to ritonavir, but not to amprenavir
V82AFST
-
the mutation is associated with decreased susceptibility to protease inhibitor lopinavir
V82E
-
with VSQNYPIVQ the turnover-number of the mutant enzyme is 60% of that of the wild-type enzyme, with VSQNYPIVQ the KM-value of the mutant enzyme is 6.9fold higher than the Km-value of the wild-type enzyme
V82F
V82F/I84V
V82I
-
occuring in HIV-1 variant, (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-3-hydroxy-4-[(7Z)-13-methoxy-1,1-dioxido-3,4,5,6,9,10-hexahydro-2H-11,1,2-benzoxathiazacyclotridecin-2-yl]-1-phenylbutan-2-yl]carbamate (GRL-216) prevented from blocking dimerization, HIV-1 resistence to (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-3-hydroxy-4-[(7Z)-13-methoxy-1,1-dioxido-3,4,5,6,9,10-hexahydro-2H-11,1,2-benzoxathiazacyclotridecin-2-yl]-1-phenylbutan-2-yl]carbamate (GRL-216)
V82L
V82LT
-
the mutation is associated with decreased susceptibility to protease inhibitor tipranavir
V82S
V82T
V82T/I84V
additional information
A28S
-
with VSQNYPIVQ the turnover-number of the mutant enzyme is 37% of that of the wild-type enzyme
A28S
-
the ratio of turnover number to Km-value for the substrate TATIMMQRGN is 1527fold lower than that for the wild-type enzyme. The ratio of turnover number to Km-value for the substrate RQGTVSFNFPQITL is 1488fold lower than that for the wild-type enzyme
C67A
-
kcat/Km ratio for KARV-Nle-Phe(NO2)-EA-Nle-NH2 as substrate is similar to that of the wild-type enzyme
D25N
-
mutation increases the equilibrium dimer dissociation constant by a factor of more than 100fold relative to wild-type. In the absence of inhibitor, NMR studies reveal clear structural differences between wild-type and mutant enzyme in the relatively mobile P1 loop (residues 79-83) and flap regions, and differential scanning calorimetric analyses show that the mutation lowers the stabilities of both the monomer and dimer folds by 5 and 7.3°C, respectively. Complexation with acetyl-Thr-Ile-Nle-r-Nle-Gln-Arg-NH2 stabilizes both dimers, the effect on their Tm is smaller for the mutant enzyme (6.2°C) than for wild-type enzyme (8.7°C). The Tm of mutant enzyme/darunavir increases by only 3°C relative to free mutant enzyme, as compared with a 22°C increase for wild-type enzyme/darunavir. Mutation increases the ligand dissociation constant of mutant enzyme/darunavir by a factor of about 1000000 relative to wild-type enzyme/darunavir
D30N
-
similar to wild-type enzyme in stability towards urea denaturation. The kcat/Km ratio for the substrate KARVLAEAMS is 113% of that for the autoproteolysis resistant variant Q7K/L33I/L63I/C67A/C95A
D30N
-
mutant of HIV-1 protease subtype B, kcat/Km is 4.2fold lower than wild-type value
D30N
-
mutant of HIV-1 protease subtype C, kcat/Km is 1.8fold lower than wild-type value
D30N
-
in treated patients, K20M, D30N, G73S, I84V, and L90M, are more prevalent in subtype B, and K20T and N88S are more prevalent in subtype F1
D30N
-
key residue mutation of drug resistance to inhibitors in clinical use
D30N
-
the mutation is associated with decreased susceptibility to protease inhibitor nelfinavir
D30N/L90M
-
mutant of HIV-1 protease subtype B, kcat/Km is 9.2fold lower than wild-type value
D30N/L90M
-
mutant of HIV-1 protease subtype C, kcat/Km is 1.9fold lower than wild-type value
D30N/N88D
-
mutant of HIV-1 protease subtype B, kcat/Km is 1.4fold lower than wild-type value
D30N/N88D
-
mutant of HIV-1 protease subtype C, kcat/Km is 1.9fold lower than wild-type value
F53L
-
site-directed mutagenesis in the flexible flap region, the mutation leads to 15% reduced catalytic efficiency, 20fold higher resistance against indinavir, and reduced dimer stability
F53L
-
the mutation is associated with decreased susceptibility to protease inhibitor saquinavir
G48V
-
the kcat/Km ratio for the substrate KARVLAEAMS is 55% of that for the autoproteolysis resistant variant Q7K/L33I/L63I/C67A/C95A
G48V
-
less loss of activity with saquinavir as inhibitor, Ki is 13.5fold higher
G48V
-
mutant enzyme with 9.3% of the activity of the wild-type enzyme with VSQNYPIVQ as substrate
G48V
-
half maximal activity at 0.7 M urea compared to 1.8 M for the wild-type enzyme
G48V
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mutation in flap region. About 30% of wild-type activity, poor inhibition by saquinavir and darunavir
G48V
-
the mutation is associated with decreased susceptibility to protease inhibitor saquinavir and nelfinavir
G48V/L90M
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mutant enzyme with 1.7% of the activity of the wild-type enzyme with VSQNYPIVQ as substrate, less loss of activity with saquinavir as inhibitor, Ki is 419fold higher than that of the wild-type enzyme
G48V/L90M
-
mutant exhibits wild-type preference for large hydrophobic residues, especially Phe, in the P1' substrate position
G73S
-
in treated patients, K20M, D30N, G73S, I84V, and L90M, are more prevalent in subtype B, and K20T and N88S are more prevalent in subtype F1
G73S
-
the mutation is associated with decreased susceptibility to protease inhibitors saquinavir, indinavir and nelfinavir
I50V
-
mutation in flap region. About 10% of wild-type activity
I50V
-
key residue mutation of drug resistance to inhibitors in clinical use
I50V
-
the mutation is associated with decreased susceptibility to protease inhibitors atazanavir, darunavir and lopinavir
I54V
-
site-directed mutagenesis of wild-type V6 enzyme, non-active-site mutation, the mutation leads to resistance against ritonavir, inhibitor binding structure analysis
I54V
-
mutation in flap region. About 40% of wild-type activity
I54V
-
the mutation is associated with decreased susceptibility to protease inhibitors indinavir and nelfinavir
I54V
the mutant enzyme is resistant against inhibition by darunavir and nelfinavir
I84V
-
mutant exhibits wild-type preference for large hydrophobic residues, especially Phe, in the P1' substrate position
I84V
-
with VSQNYPIVQ the turnover-number of the mutant enzyme is 19% of that of the wild-type enzyme, with VSQNYPIVQ the KM-value of the mutant enzyme is 7.2fold higher than the Km-value of the wild-type enzyme
I84V
-
site-directed mutagenesis of wild-type V6 enzyme, active-site mutation, the mutation leads to resistance against ritonavir, the mutant shows 10fold reduced catalytic effciency compared to the wild-type enzyme, inhibitor binding structure analysis
I84V
-
site-directed mutagenesis, kinetic and structural studies
I84V
-
HIV-1 pNL4-3 clones with a single V82L or I84V mutation are phenotypically resistant to A-790742 and ritonavir
I84V
-
in treated patients, K20M, D30N, G73S, I84V, and L90M, are more prevalent in subtype B, and K20T and N88S are more prevalent in subtype F1
I84V
-
occuring in HIV-1 variant, (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-3-hydroxy-4-[(7Z)-13-methoxy-1,1-dioxido-3,4,5,6,9,10-hexahydro-2H-11,1,2-benzoxathiazacyclotridecin-2-yl]-1-phenylbutan-2-yl]carbamate (GRL-216) prevented from blocking dimerization, HIV-1 resistence to (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-3-hydroxy-4-[(7Z)-13-methoxy-1,1-dioxido-3,4,5,6,9,10-hexahydro-2H-11,1,2-benzoxathiazacyclotridecin-2-yl]-1-phenylbutan-2-yl]carbamate (GRL-216)
I84V
-
the mutation is associated with decreased susceptibility to protease inhibitors darunavir and tipranavir
K20R
-
site-directed mutagenesis of wild-type V6 enzyme, non-active-site mutation, inhibitor binding structure analysis
K20R
-
in untreated patients, mutations L10V, K20R, and M36I are more frequent in subtype F1, while L63P, A71T, and V77I are more prevalent in subtype B
L10I/L63P/A71V/G73S/I84V/L90M
-
mutations in drug-resistant clinical isolates
L33F
-
site-directed mutagenesis of wild-type V6 enzyme, non-active-site mutation, inhibitor binding structure analysis
L33F
-
the mutation is associated with decreased susceptibility to protease inhibitors atazanavir, darunavir, tipranavir and lopinavir
L63P
-
site-directed mutagenesis of wild-type V6 enzyme, non-active-site mutation, inhibitor binding structure analysis
L63P
-
in untreated patients, mutations L10V, K20R, and M36I are more frequent in subtype F1, while L63P, A71T, and V77I are more prevalent in subtype B
L76V
-
virus with mutation L76V in protease or I437T/V in gag may be already resistant to darunavir
L76V
-
the mutation is associated with decreased susceptibility to protease inhibitors atazanavir, darunavir, indinavir and lopinavir
L90M
-
the kcat/Km ratio for the substrate KARVLAEAMS is 44% of that for the autoproteolysis resistant variant Q7K/L33I/L63I/C67A/C95A. Half maximal activity at 1.0 M urea compared to 1.8 M for the wild-type enzyme
L90M
-
with VSQNYPIVQ the turnover-number of the mutant enzyme is 6% of that of the wild-type enzyme, with VSQNYPIVQ the KM-value of the mutant enzyme is 76% of the Km-value of the wild-type enzyme
L90M
-
mutant enzyme with 7.9% of the activity of the wild-type enzyme with VSQNYPIVQ as substrate, less loss of activity with saquinavir as inhibitor, Ki is 3fold higher
L90M
-
site-directed mutagenesis of wild-type V6 enzyme, non-active-site mutation, inhibitor binding structure analysis
L90M
-
mutant of HIV-1 protease subtype B, kcat/Km is nearly identical to wild-type value
L90M
-
mutant of HIV-1 protease subtype C, kcat/Km is 1.6fold lower than wild-type value
L90M
-
in treated patients, K20M, D30N, G73S, I84V, and L90M, are more prevalent in subtype B, and K20T and N88S are more prevalent in subtype F1
L90M
-
the mutation is associated with decreased susceptibility to protease inhibitors saquinavir, indinavir and nelfinavir
L90M
the mutant enzyme is resistant against inhibition by darunavir and tipranavir
M36I
-
site-directed mutagenesis of wild-type V6 enzyme, non-active-site mutation, inhibitor binding structure analysis
M36I
-
in untreated patients, mutations L10V, K20R, and M36I are more frequent in subtype F1, while L63P, A71T, and V77I are more prevalent in subtype B
M46I
-
site-directed mutagenesis of wild-type V6 enzyme, non-active-site mutation, the mutation leads to resistance against ritonavir, inhibitor binding structure analysis
M46L
-
the kcat/Km ratio for the substrate KARVLAEAMS is 63% of that for the autoproteolysis resistant variant Q7K/L33I/L63I/C67A/C95A
M46L
the mutant enzyme is resistant against inhibition by darunavir and saquinavir
N88D
-
mutant with significantly increased stability with half-maximal activity at 3.1 mM urea compared to 1.8 M urea for the wild-type enzyme. The kcat/Km ratio for the substrate KARVLAEAMS is 39% of that for the autoproteolysis resistant variant Q7K/L33I/L63I/C67A/C95A
N88D
-
mutant of HIV-1 protease subtype B, kcat/Km is 1.4fold higher than wild-type value
N88D
-
mutant of HIV-1 protease subtype C, kcat/Km is 1.7fold lower than wild-type value
N88D/L90M
-
mutant of HIV-1 protease subtype B, kcat/Km is 1.6fold lower than wild-type value
N88D/L90M
-
mutant of HIV-1 protease subtype C, kcat/Km is 1.1fold higher than wild-type value
N88S
-
in treated patients, K20M, D30N, G73S, I84V, and L90M, are more prevalent in subtype B, and K20T and N88S are more prevalent in subtype F1
N88S
-
the mutation is associated with decreased susceptibility to protease inhibitor indinavir
Q7K/L33I/L63I/C67A/C95A
-
the kinetic parameters are nearly identical to those of the native enzyme. Half maximal activity at 1.9 M urea compared to 1.8 M for the wild-type enzyme
Q7K/L33I/L63I/C67A/C95A
-
mutant enzyme with restricted autoproteolysis, self-degradation
Q7K/L33I/L63I/C67A/C95A
mutant enzyme with restricted autoproteolysis, self-degradation
Q7K/L33I/L63I/C67A/C95A
-
site-directed mutagenesis, mutations lead to stabilization of the enzyme for kinetic and structural studies
Q7K/L33I/L63I/C67A/C95A
-
mutations prevent autoproteolysis and cysteine thiol oxidation
Q7K/L33I/L63I/C67A/C95A
-
reduced autoproteolysis and aggregation, mutations do not alter the inhibitor binding site and the mutant protein has kinetic parameters and stability indistinguishable from those of the unsubstituted enzyme
Q7K/L33I/L63I/C67A/C95A
the mutations diminish the autoproteolysis and prevent cysteine-thiol oxidation of the HIV-1 protease
V32I
-
significant difference in subsite selection compared to wild-type enzyme
V32I
-
site-directed mutagenesis of wild-type V6 enzyme, the mutation leads to resistance against ritonavir, inhibitor binding structure analysis
V32I
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the mutation is associated with decreased susceptibility to protease inhibitors atazanavir, darunavir, lopinavir and indinavir
V32I
site-directed mutagenesis, mutant enzyme structure modelling
V32I/I47V/V82I
the mutations mimic the inhibitor binding site of HIV-2 protease and shows increased kcat values compared to the wild type enzyme
V32I/I47V/V82I
the three mutations do not significantly alter the interaction between inhibitor amprenavir and the enzyme
V82A
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drug resistance with ritonavir, saquinavir and indinavir
V82A
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with VSQNYPIVQ the turnover-number of the mutant enzyme is 40% of that of the wild-type enzyme, with VSQNYPIVQ the KM-value of the mutant enzyme is 2.8fold higher than the Km-value of the wild-type enzyme
V82A
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site-directed mutagenesis of wild-type V6 enzyme, the mutation leads to resistance against ritonavir, inhibitor binding structure analysis
V82A
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site-directed mutagenesis, kinetic and structural studies
V82A
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mutation isolated in South African subtype C protease, no significant impact on proteolytic abilities. Decrease in binding abilities for inhibitors saquinavir, ritonavir, indinavir, and nelfinavir
V82F
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reduced dimer stability relative to the autolysis resistant mutant Q7K/L33I/L631I at pH 7.0
V82F
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mutation at the active site resulting in a conformational change of 79's loop region and displacement of inhibitor lopinavir from its proper binding site, changes lead to rotation of the side-chains of residues D25 and I50'. The conformation of the binding cavity is deformed asymmetrically and some interactions between protease and lopinavir are destroyed
V82F
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the mutation is associated with decreased susceptibility to protease inhibitors atazanavir and nelfinavir
V82F/I84V
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reduced dimer stability relative to the autolysis resistant mutant Q7K/L33I/L631I at pH 7.0
V82F/I84V
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mutation isolated in South African subtype C protease, no significant impact on proteolytic abilities. Decrease in binding abilities for inhibitors saquinavir, ritonavir, indinavir, and nelfinavir to levels significantly lower than that required for effective inhibition
V82F/I84V
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the mutation leads to resistance to standard antiretroviral drugs
V82L
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HIV-1 pNL4-3 clones with a single V82L or I84V mutation are phenotypically resistant to A-790742 and ritonavir
V82L
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mutation is present with increased frequency in isolates from children compared to isolates from adults infected with both subtypes B and F1
V82S
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similar to wild-type enzyme in stability towards urea denaturation. The kcat/Km ratio for the substrate KARVLAEAMS is 24% of that for the autoproteolysis resistant variant Q7K/L33I/L63I/C67A/C95A
V82T
the mutant enzyme is resistant against inhibition by darunavir
V82T/I84V
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mutant exhibits wild-type preference for large hydrophobic residues, especially Phe, in the P1' substrate position
V82T/I84V
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reduced dimer stability relative to the autolysis resistant mutant Q7K/L33I/L631I at pH 7.0
additional information
truncated enzyme PR-(5-95): displays severe aggregation. The catalytic activity is similar to that of wild-type enzyme. The lower kcat/Km observed for Pr-(5-99) using five different substrates suggests that only a small fraction of the protein contrubutes to the observed activity. PR-(1-95) does not exhibit detectable cleavage of any of the substrates tested
additional information
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truncated enzyme PR-(5-95): displays severe aggregation. The catalytic activity is similar to that of wild-type enzyme. The lower kcat/Km observed for Pr-(5-99) using five different substrates suggests that only a small fraction of the protein contrubutes to the observed activity. PR-(1-95) does not exhibit detectable cleavage of any of the substrates tested
additional information
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three chimeric HIV proteases are constructed by substituting amino acid residues in the HIV type 1 protease sequence with the corresponding residues from HIV type 2 in the region spanning residues 31-37 and in the active site cavity. Crystallographic analysis reveals that substitution of residues 31-37 (30's loop) with those of HIV-2 protease renders the chimera similar to HIV-2 protease in both the inhibitor binding affinity and mode of binding (two inhibitor molecules per protease dimer). However, further substitution of active site residues 47 and 82 has a compensatory effect which restores the HIV-1-like inhibitor binding mode
additional information
enzyme PR mutant with mutations Q7K/L33I/L63I/C67A/C95A and the additional mutation D25N/C2-S-S-C97, in which the terminal beta-strand is linked through a disulfide bridge, is less prone to aggregation, even at a relatively high protein concentration of about 1 mM
additional information
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enzyme PR mutant with mutations Q7K/L33I/L63I/C67A/C95A and the additional mutation D25N/C2-S-S-C97, in which the terminal beta-strand is linked through a disulfide bridge, is less prone to aggregation, even at a relatively high protein concentration of about 1 mM
additional information
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observed enzyme mutations of HIV-1 protease, either naturally occuring or induced by drug therapy, are found in regions that are not structurally designed to withstand unfolding. These mutations are especially likely to occur in the flap region, a part of the protein which is not essentiall for stability of the protein, but does contribute significantly to the stability of the protease-drug complexes
additional information
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proteases with modified aspartic acid analogues at Asp25 or Asp125. Introduction of the beta-methyl moiety alters the protease function to varying extents depending upon ist orientation. While a beta-methyl group in the erythro orientation is the least deleterious to the specific activity of the protease, a beta-methyl group in the threo orientation, present in the modified proteins containing threo-beta-methylaspartate and beta,beta-dimethylaspartate, results in specific activities between 0 and 45% of that of the wild-type depending upon the substrate and the substituted active site position
additional information
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constuction of a hybrid comprising HIV-1 and HIV-2 retropepsin, overview
additional information
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protease lacking the terminal residues 1-4 and 96-99 exhibits a stable monomer fold
additional information
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comparison of the differences between subtypes B and F1 in the acquisition of major and minor protease inhibitor-associated resistance mutations and other polymorphisms in the protease gene. In untreated patients, mutations L10V, K20R, and M36I are more frequent in subtype F1, while L63P, A71T, and V77I are more prevalent in subtype B. In treated patients, K20M, D30N, G73S, I84V, and L90M, are more prevalent in subtype B, and K20T and N88S are more prevalent in subtype F1. A higher proportion of subtype F1 than of subtype B strains containing other polymorphisms is observed. V82L mutation is present with increased frequency in isolates from children compared to isolates from adults infected with both subtypes
additional information
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construction of chimeric viruses using patient-derived gag-protease sequences amplified from plasma HIV RNA and inserted into an NL4-3 backbone. The chimeric viruses generated from elite controllers display lower replication capacity than viruses from chronic progressors. Human leukocyte antigen system allele HLA-B*57 is associated with lower replication capacity than other alleles in both elite controllers and chronic progressor groups. Chimeric viruses from allele B*57 elite controllers demonstrate lower replication capacity than viruses from allele B*57 chronic progressors. Cytotoxic T-lymphocyte selection pressure on gag-protease alters virus replication capacity, and HIV-specific cytotoxic T-lymphocytes inducing escape mutations with fitness costs in this region may be important for strict viremia control in elite controllers of HIV
additional information
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isolation of subtype G viruses from patients with diverse amino acid combinations at codons 71, 74, 89 and 90. In isolates displaying 89I/V in combination with A71 or T74, a reversal to subtype G wild-type 89M is observed after growth in the absence of protease inhibitor. The presence of 71T in one isolate and 74S in another allows the persistence of 89I. Mutation 90M confers intermediate but significant degrees of drug resistance to ritonavir and nelfinavir in subtype G viruses. The combination of 71T or 74S, 89I and 90M results in higher levels of resistance to those protease inhibitors. 71T or 74S may stabilize 89I in the protease of subtype G
additional information
modelling of PR1 mutant structures containing V32I and L76M substitutions reveals a cooperative mechanism leading to structural deformation of flap-residue 45 that can modify PR2 flexibility
additional information
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modelling of PR1 mutant structures containing V32I and L76M substitutions reveals a cooperative mechanism leading to structural deformation of flap-residue 45 that can modify PR2 flexibility
