Crystallization (Comment) | Organism |
---|---|
purified enzyme complexed with inhibitor N6-methyl-N6-1-naphthylpyrido[2,3-d]pyrimidine-2,4,6-triamine, and NADPH, hanging drop vapor diffusion method, mixing of 11.4-14.1 mg/ml protein in 50 mM MES, pH 6.0, 100 ml KCl, and a tenfold excess of NADPH and inhibitor, with reservoir solution containiing 35% PEG 2000, 49 mM MES, pH 6.0, and 100 mM KCl, equilibration against a reservoir solution consisting of 0.1 M HEPES pH 7.5, 25% PEG 2000 MM, X-ray diffraction structure determination and analyis at 1.61 A resolution, modeling | Pneumocystis carinii |
purified enzyme complexed with inhibitor N6-methyl-N6-1-naphthylpyrido[2,3-d]pyrimidine-2,4,6-triamine, and NADPH, X-ray diffraction structure determination and analyis | Pneumocystis jirovecii |
purified enzyme in ternary complex with inhibitors N6-methyl-N6-(4-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine or N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine, and NADPH, hanging drop vapor diffusion method, mixing of 7.9 mg/ml protein in 100 mM K2HPO4, pH 6.9, and 30% saturated ammonium sufate, and a tenfold excess of NADPH and inhibitor, with reservoir solution consisting of 100 mM K2HPO4, pH 6.9, 60% saturated ammonium sulfate, and 3% v/v ethanol, X-ray diffraction structure determination and analysis at 1.54 A resolution, modeling | Homo sapiens |
Protein Variants | Comment | Organism |
---|---|---|
F69N | site-directed mutagenesis | Pneumocystis carinii |
Inhibitors | Comment | Organism | Structure |
---|---|---|---|
additional information | design and synthesis of a series of bicyclic pyrido[2,3-d]pyrimidines that contain an N6-(substituted phenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine scaffold in which the substituted aniline is directly attached to the 6-position of the pyrido[2,3-d] pyrimidine ring as selective and potent inhibitors of pathogenic sources of dihydrofolate reductase (DHFR) such as Pneumocystis jirovecii, a causative agent of pneumonia in HIV/AIDS patients. Analysis of the interactions that enhance the selectivity of binding and to directly compare the binding of the most potent analogue in the series, N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine with enzyme from Homosapiens, Pneumocystis carinii, and Pneumocystis jirovecii, overview | Homo sapiens | |
additional information | design and synthesis of a series of bicyclic pyrido[2,3-d]pyrimidines that contain an N6-(substituted phenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine scaffold in which the substituted aniline is directly attached to the 6-position of the pyrido[2,3-d] pyrimidine ring as selective and potent inhibitors. Analysis of the interactions that enhance the selectivity of binding and to directly compare the binding of the most potent analogue in the series, N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine with enzyme from Homosapiens, Pneumocystis carinii, and Pneumocystis jirovecii, overview | Pneumocystis carinii | |
additional information | design and synthesis of a series of bicyclic pyrido[2,3-d]pyrimidines that contain an N6-(substituted phenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine scaffold in which the substituted aniline is directly attached to the 6-position of the pyrido[2,3-d] pyrimidine ring as selective and potent inhibitors of the enzyme. Analysis of the interactions that enhance the selectivity of binding and to directly compare the binding of the most potent analogue in the series, N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine with enzyme from Homosapiens, Pneumocystis carinii, and Pneumocystis jirovecii, overview | Pneumocystis jirovecii | |
N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine | binding complex structure analysis, the trifluorophenyl ring occupies a position near the enzyme cofactor-binding site, with close intermolecular contacts with Asp21, Ser59 and Ile60 | Homo sapiens | |
N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine | binding complex structure analysis | Pneumocystis carinii | |
N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine | binding complex structure analysis | Pneumocystis jirovecii | |
N6-methyl-N6-(4-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine | binding complex structure analysis | Homo sapiens | |
N6-methyl-N6-(4-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine | binding complex structure analysis | Pneumocystis carinii | |
N6-methyl-N6-(4-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine | binding complex structure analysis | Pneumocystis jirovecii | |
N6-methyl-N6-1-naphthylpyrido[2,3-d]pyrimidine-2,4,6-triamine | binding complex structure analysis | Homo sapiens | |
N6-methyl-N6-1-naphthylpyrido[2,3-d]pyrimidine-2,4,6-triamine | binding complex structure analysis | Pneumocystis carinii | |
N6-methyl-N6-1-naphthylpyrido[2,3-d]pyrimidine-2,4,6-triamine | binding complex structure analysis | Pneumocystis jirovecii | |
N6-methyl-N6-phenylpyrido[2,3-d]pyrimidine-2,4,6-triamine | - |
Homo sapiens | |
N6-methyl-N6-phenylpyrido[2,3-d]pyrimidine-2,4,6-triamine | - |
Pneumocystis carinii | |
N6-methyl-N6-phenylpyrido[2,3-d]pyrimidine-2,4,6-triamine | - |
Pneumocystis jirovecii | |
piritrexim | - |
Homo sapiens | |
piritrexim | - |
Pneumocystis carinii | |
piritrexim | - |
Pneumocystis jirovecii |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
7,8-dihydrofolate + NADPH + H+ | Homo sapiens | - |
5,6,7,8-tetrahydrofolate + NADP+ | - |
r | |
7,8-dihydrofolate + NADPH + H+ | Pneumocystis carinii | - |
5,6,7,8-tetrahydrofolate + NADP+ | - |
r | |
7,8-dihydrofolate + NADPH + H+ | Pneumocystis jirovecii | - |
5,6,7,8-tetrahydrofolate + NADP+ | - |
r |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | P00374 | - |
- |
Pneumocystis carinii | P16184 | - |
- |
Pneumocystis jirovecii | Q9UUP5 | - |
- |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
7,8-dihydrofolate + NADPH + H+ | - |
Homo sapiens | 5,6,7,8-tetrahydrofolate + NADP+ | - |
r | |
7,8-dihydrofolate + NADPH + H+ | - |
Pneumocystis carinii | 5,6,7,8-tetrahydrofolate + NADP+ | - |
r | |
7,8-dihydrofolate + NADPH + H+ | - |
Pneumocystis jirovecii | 5,6,7,8-tetrahydrofolate + NADP+ | - |
r |
Synonyms | Comment | Organism |
---|---|---|
DHFR | - |
Homo sapiens |
DHFR | - |
Pneumocystis carinii |
DHFR | - |
Pneumocystis jirovecii |
hDHFR | - |
Homo sapiens |
pcDHFR | - |
Pneumocystis carinii |
pcDHFR | - |
Pneumocystis jirovecii |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
NADP+ | - |
Homo sapiens | |
NADP+ | - |
Pneumocystis carinii | |
NADP+ | - |
Pneumocystis jirovecii | |
NADPH | - |
Homo sapiens | |
NADPH | - |
Pneumocystis carinii | |
NADPH | - |
Pneumocystis jirovecii |