1IA2

Candida albicans dihydrofolate reductase complexed with dihydro-nicotinamide-adenine-dinucleotide phosphate (NADPH) and 5-[(4-METHYLPHENYL)SULFANYL]-2,4-QUINAZOLINEDIAMINE (GW578)

1IA2 の概要

• エントリーDOI: 10.2210/pdb1ia2/pdb
• 関連するPDBエントリー: 1AI9 1AOE 1IA1 1IA3 1IA4
• 分子名称: DIHYDROFOLATE REDUCTASE, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 5-[(4-METHYLPHENYL)SULFANYL]-2,4-QUINAZOLINEDIAMINE, ... (5 entities in total)
• 機能のキーワード: oxidoreductase, antifungal target, reductase
• 由来する生物種: Candida albicans
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 46835.10

構造登録者

Whitlow, M.,Howard, A.J.,Kuyper, L.F. (登録日: 2001-03-22, 公開日: 2001-04-11, 最終更新日: 2023-08-09)

主引用文献

Whitlow, M.,Howard, A.J.,Stewart, D.,Hardman, K.D.,Chan, J.H.,Baccanari, D.P.,Tansik, R.L.,Hong, J.S.,Kuyper, L.F.
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
J.Med.Chem., 44:2928-2932, 2001

PubMed Abstract: 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.

PubMed: 11520201
DOI: 10.1021/jm0101444

実験手法

X-RAY DIFFRACTION (1.82 Å)