1ia2
|
Candida albicans dihydrofolate reductase complexed with dihydro-nicotinamide-adenine-dinucleotide phosphate (NADPH) and 5-[(4-METHYLPHENYL)SULFANYL]-2,4-QUINAZOLINEDIAMINE (GW578)
OverviewOverview
X-ray crystallographic analysis of 5-(4'-substituted, phenyl)sulfanyl-2,4-diaminoquinazoline inhibitors in ternary complex with, Candida albicans dihydrofolate reductase (DHFR) and NADPH revealed two, distinct modes of binding. The two compounds with small 4'-substituents (H, and CH3) were found to bind with the phenyl group oriented in the plane of, the quinazoline ring system and positioned adjacent to the C-helix. In, contrast, the more selective inhibitors with larger 4'-substituents, (tert-butyl and N-morpholino) were bound to the enzyme with the phenyl, group perpendicular to the quinazoline ring and positioned in the region, of the active site that typically binds the dihydronicotinamide moiety of, NADPH. The cofactor appeared bound to DHFR but with the disordered, dihydronicotinamide swung away from the protein surface and into solution., This unusual inhibitor binding mode may play an important role in the high, DHFR selectivity of these compounds and also may provide new ideas for, inhibitor design.
About this StructureAbout this Structure
1IA2 is a Single protein structure of sequence from Candida albicans with NDP, TQ4 and MES as ligands. Active as Dihydrofolate reductase, with EC number 1.5.1.3 Full crystallographic information is available from OCA.
ReferenceReference
X-Ray crystal structures of Candida albicans dihydrofolate reductase: high resolution ternary complexes in which the dihydronicotinamide moiety of NADPH is displaced by an inhibitor., Whitlow M, Howard AJ, Stewart D, Hardman KD, Chan JH, Baccanari DP, Tansik RL, Hong JS, Kuyper LF, J Med Chem. 2001 Aug 30;44(18):2928-32. PMID:11520201
Page seeded by OCA on Tue Nov 20 17:12:30 2007