1vj3
From Proteopedia
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|PDB= 1vj3 |SIZE=350|CAPTION= <scene name='initialview01'>1vj3</scene>, resolution 2.10Å | |PDB= 1vj3 |SIZE=350|CAPTION= <scene name='initialview01'>1vj3</scene>, resolution 2.10Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene> | + | |LIGAND= <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=TAB:ACETIC+ACID+N-[2-CHLORO-5-[6-ETHYL-2,4-DIAMINO-PYRIMID-5-YL]-PHENYL]-[BENZYL-TRIAZEN-3-YL]ETHYL+ESTER'>TAB</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] </span> |
|GENE= C-DNA P.CARINII DHFR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4754 Pneumocystis carinii]) | |GENE= C-DNA P.CARINII DHFR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4754 Pneumocystis carinii]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1vj3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1vj3 OCA], [http://www.ebi.ac.uk/pdbsum/1vj3 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1vj3 RCSB]</span> | ||
}} | }} | ||
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[[Category: Queener, S F.]] | [[Category: Queener, S F.]] | ||
[[Category: Rak, D.]] | [[Category: Rak, D.]] | ||
| - | [[Category: NDP]] | ||
| - | [[Category: TAB]] | ||
[[Category: molecular modeling]] | [[Category: molecular modeling]] | ||
[[Category: nadph]] | [[Category: nadph]] | ||
[[Category: tab]] | [[Category: tab]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:25:10 2008'' |
Revision as of 21:25, 30 March 2008
| |||||||
| , resolution 2.10Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Gene: | C-DNA P.CARINII DHFR (Pneumocystis carinii) | ||||||
| Activity: | Dihydrofolate reductase, with EC number 1.5.1.3 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
STRUCTURAL STUDIES ON BIO-ACTIVE COMPOUNDS. CRYSTAL STRUCTURE AND MOLECULAR MODELING STUDIES ON THE PNEUMOCYSTIS CARINII DIHYDROFOLATE REDUCTASE COFACTOR COMPLEX WITH TAB, A HIGHLY SELECTIVE ANTIFOLATE.
Overview
The crystal structure of the ternary complex of NADPH, the potent antifolate [2, 4-diamino-5- inverted question mark3-[3-(2-acetyloxyethyl)-3-benzyltriazen-1-yl]-4 -chloroph enyl inverted question mark-6-ethylpyrimidine] (TAB, 1) and Pneumocystis carinii dihydrofolate reductase (pcDHFR), refined to 2.1 A resolution, reveals that TAB binds similar to the antifolates trimethoprim and methotrexate. These data also reveal multiple conformations for the binding geometry of TAB with two preferred orientations of the acetyloxy and benzyl groups that results from a 180 degrees rotation about the N2-N3 triazenyl bond. The methyl of the acetyloxy and benzyl ring of TAB probes large hydrophobic regions of the p-aminobenzoyl folate binding pocket of the active site, in particular the region near Phe69, which is unique to the pcDHFR sequence. These results confirm prior molecular modeling investigations of the binding of TAB to pcDHFR that identified four low-energy binding geometries, two involving rotations about the terminal N(2)-N(3) triazenyl linkage and two involving atropisomerism about the pivotal pyrimethamine-phenyl bond. The primary differences in the molecular dynamics (MD) models and those observed in this crystal complex result from small conformational changes in active-site residues on energy minimization. However, two MD models place the acetyloxy and benzyl ring groups in a region of the active site between the cofactor-binding region and the p-aminobenzoyl folate pocket; an orientation never observed in any DHFR crystal structure to date. These conformers interact with solvent near the enzyme surface and are probably not observed due to the loss of specific hydrogen bonds with the enzyme. The high species pcDHFR selectivity of TAB could be the result of ligand flexibility that enables multiple binding orientations at the enzyme active site. Further modification of the acetyloxy region of TAB could increase its potency and selectivity for pcDHFR.
About this Structure
1VJ3 is a Single protein structure of sequence from Pneumocystis carinii. This structure supersedes the now removed PDB entry 1D8R. Full crystallographic information is available from OCA.
Reference
Structural studies on bioactive compounds. 30. Crystal structure and molecular modeling studies on the Pneumocystis carinii dihydrofolate reductase cofactor complex with TAB, a highly selective antifolate., Cody V, Chan D, Galitsky N, Rak D, Luft JR, Pangborn W, Queener SF, Laughton CA, Stevens MF, Biochemistry. 2000 Apr 4;39(13):3556-64. PMID:10736154
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