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3.4.23.46: memapsin 2

This is an abbreviated version!
For detailed information about memapsin 2, go to the full flat file.

Word Map on EC 3.4.23.46

Reaction

broad endopeptidase specificity. Cleaves Glu-Val-Asn-Leu-/-Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein =

Synonyms

alpha-secretase, amyloid precursor protein secretase, APP secretase, Asec-1A, aspartic protease BACE, aspartic protease BACE1, Aspartic proteinase, aspartic proteinase BACE1, BACE, BACE 1, BACE I, BACE-1, BACE-2, BACE1, BACE1/beta-secretase, BACE2, beta protein amyloidogenase, beta secretase, beta-amyloid cleaving enzyme, beta-amyloid cleaving enzyme 1, beta-amyloid cleaving enzyme-1, beta-amyloid precursor protein cleavage enzyme 1, beta-amyloid precursor protein cleaving enzyme, beta-amyloid protein precursor secretase, beta-amyloid-cleaving enzyme, beta-amyloid-converting enzyme-1, beta-APP cleaving enzyme 1, beta-secretase, beta-secretase enzyme 1, beta-secretase-1, beta-site Alzheimer's amyloid precursor protein cleaving enzyme 1 (BACE1), beta-site amyloid cleaving enzyme, beta-site amyloid precursor protein cleavage enzyme, beta-site amyloid precursor protein cleaving enzyme, beta-site amyloid precursor protein cleaving enzyme 1, beta-site amyloid precursor protein cleaving enzyme-1, beta-site amyloid precursor protein enzyme 1, beta-site amyloid precursor protein-cleaving enzyme, beta-site amyloid precursor protein-cleaving enzyme 1, beta-site APP (amyloid precursor protein) cleaving enzyme, beta-site APP cleaving enzyme, beta-site APP cleaving enzyme 1, beta-site APP cleaving enzyme-1, beta-site APP-cleaving enzyme 1, D-aspartyl-beta-amyloid secretase, gamma-secretase, memapsin 1, memapsin 2, memapsin2, membrane-bound aspartic protease, NACE1, presenilin 1, presenilin-1, presenilin-2, protease Asp2, proteinase BACE1

ECTree

     3 Hydrolases
         3.4 Acting on peptide bonds (peptidases)
             3.4.23 Aspartic endopeptidases
                3.4.23.46 memapsin 2

Crystallization

Crystallization on EC 3.4.23.46 - memapsin 2

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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
6 x His-tagged proBACE1
BACE-1 in complex with inhibitor N-[(1S,2S,4R)-4-((S)-1-benzylcarbamoyl-2-methylpropylcarbamoyl)-1-(3,5-difluoro-phenoxymethyl)-2-hydroxy-4-(2-methoxy-ethoxy)-butyl]-5-(methanesulfonyl-methylamino)-N'-((R)-1-phenyl-ethyl)-isophthalamide
conformational study of BACE1 inhibitor shown, molecular surface model and stereoview indicated
conformational study of BACE1 inhibitor, molecular surface model and stereoview indicated
evolutionary trace analysis identifies group-specific residues in the ligand binding sites of BACE1, and BACE2, EC 3.4.23.45.The residues are Pro70, Ile110, Ile126, andAsn233 of BACE1 substituting Lys86, Leu126, Leu142, and Leu246 of BACE2, respectively.These group-specific residues would be the reason for cleavage site selectivity in BACE1 and BACE2 biological function
hanging drop vapor diffusion method, using 6% (w/v) PEG3350, 0.1 M sodium acetate, pH 5.4
in complex with inhibitor (2R,4S)-N-butyl-4-[(2S,5S,7R)-2,7-dimethyl-3,15-dioxo-1,4-diazacyclopentadecan-5-yl]-4-hydroxy-2-methylbutanamide
in complex with inhibitor (2S)-2-((3R)-3-acetamido-3-isobutyl-2-oxo-1-pyrrolidinyl)-N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-2-(1,2,3,4-tetrahydro-3-isoquinolinyl)ethyl)-4-phenylbutanamide
in complex with inhibitor (3S,14R,16S)-16-[(1R)-1-hydroxy-2-([3-(1-methylethyl)benzyl]amino)ethyl]-3,4,14-trimethyl-1,4-diazacyclohexadecane-2,5-dione. The lipophilic isopropylbenzyl moiety of inhibitor is bound into the P2' subsite, lined on one side by the flap residues Val69, Pro70, Tyr71 and Thr72 and, on the other side, by Tyr198. In addition to hydrophobic contacts to Ser35, Val69, Tyr71 and Tyr198, this P' group is rather rigid, the position and orientation of the benzyl ring is not optimal for strong pi-stacking interactions with either Tyr71 or Tyr198
in complex with inhibitor (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5H-spiro[chromeno[2,3-b]pyridine-5,4-oxazol]-2-amine. The aminooxazoline unit engages in hydrogen-bonding interactions with the catalytic aspartic acid residues of the enzyme, and the nitrogen atom of the 2-pyridyl-3-fluoro group interacts with Ser229 via a bridging water molecule in the S3 pocket
in complex with inhibitor 6-[(3R,4S)-3-benzyl-4-hydroxy-5-oxo-5-[[3-(2H-tetrazol-5-yl)phenyl]amino]pentanoyl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-4-oxo-4H-pyran-2-carboxamide. The P3 benzene ring tightly occupies the S3 sub-pocket of BACE1. Particularly, the fluorine atom of the compound seems to interact with the side chains of the hydrophobic amino acids Ala335 and Tyr14
in complex with inhibitor N-(4-([4-(cyclohexylamino)-1-(3-fluorophenyl)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-en-8-yl]methyl)phenyl)acetamide. Inhibitor interacts with the catalytic residues via bridging water molecules
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in complex with inhibitor N-[(1S,2R)-1-benzyl-2-hydroxy-3-[(3-ethoxybenzyl)amino]propyl]-5-[methyl(methylsulfonyl)amino]-N'-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide
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in complex with inhibitor N-[(2S)-1-[[(3S)-1-(butan-2-ylamino)-3-hydroxy-1-oxobutan-2-yl]amino]-3-phenylpropan-2-yl]-5-[methyl(methylsulfonyl)amino]-N'-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide, to 2.2 A resolution. The amine functionality of the reduced amide isostere forms two tight hydrogen bonds with active site aspartic acid Asp228. The other active site Asp32 is not directly interacting with the reduced amide isostere. Asp32 is extensively hydrogen bonded the amide nitrogen of Gly34, the hydroxyl group of Ser35, and the amide nitrogen of Gly230. These interactions appear to lock Asp32 in a rigid conformation
in complex with inhibitor N-[2-methyl-5-[(6-phenylpyrimidin-4-yl)amino]phenyl]methanesulfonamide. The catalytic aspartate residues in the acitve site are not engaged in inhibitor binding
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in complex with inhibitor N1-((R)-1-(4-fluorophenyl)ethyl)-N3-((2S,3S)-3-hydroxy-4-(4-((R)-1-hydroxy ethyl)-1H-1,2,3-triazol-1-yl)-1-phenylbutan-2-yl)-5-(N-methylmethylsulfonamido) isophthalamide. Residues Pro70 and Thr72 located in the flap region are critical components for binding with inhibitors. The phenyl group of the compound occupies the S1 region of BACE1, the hydroxyl of central core can form effective hydrogen bonds with active site aspartic acid residue Asp228
in complex with inhibitor N3-[(1S,2R)-1-benzyl-2-hydroxy-3-[[(1S,2S)-2-hydroxy-1-(isobutylcarbamoyl)propyl]amino]propyl]-5-[methyl(methylsulfonyl)amino]-N1 -[(1R)-1-phenylpropyl]benzene-1,3-dicarboxamide
in complex with inhibitor OM00-3
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in complex with inhibitor OM99-2
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inhibitor binding site depicted, enhanced affinity by propyloxyphenyl substituent and projection into the S1-S3 pocket of the BACE1 site confirmed, molecular surface model and stereoview indicated
molecular docking and structure-activity relationship studies. A pyrrolidinyl side group at the P3' and P4' positions of the inhibitors are favored for strong inhibition and a small aromatic group at the P4 position is also essential to the potency
molecular docking studies of inhibitors. In the predicted binding orientation, the carbazole moiety of molecule N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-3,4-dichloro-N-phenylbenzamide creates hydrophobic interactions with Tyr198, Ile226, Thr329 and Val332. The compound is anchored to the opposite side of the active pocket through additional apolar interactions between its N-phenylbenzamide region and Phe108, Ile118, Trp115, Tyr72, Gly11 and Thr232. The ligand creates two hydrogen bonds, one between its hydroxyl group and one of the two catalytic aspartic residues of BACE1, Asp228, and the other between the carbonyl moiety and Thr71 of the flap loop
molecular modeling using PDB-structures 2B8L and 3FKT, with inhibitor 6-fluoro-2-(3-(7-fluoroimidazo[1,2-a]pyridin-2-yl)phenyl)-1H-benzo[d]imidazole
stereoview of the X-ray crystal structure of inhibitor complex with memapsin 2 indicated
structure of the active form of BACE1, dehydrated form characterized, enzyme-inhibitor complex analyzed
vapor diffusion method
in complex with inhibitor (2S)-2-((3R)-3-acetamido-3-isobutyl-2-oxo-1-pyrrolidinyl)-N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-2-(1,2,3,4-tetrahydro-3-isoquinolinyl)ethyl)-4-phenylbutanamide
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