1DG8

DIHYDROFOLATE REDUCTASE OF MYCOBACTERIUM TUBERCULOSIS COMPLEXED WITH NADPH

1DG8 の概要

• エントリーDOI: 10.2210/pdb1dg8/pdb
• 関連するPDBエントリー: 1DF7 1DG5 1DG7
• 分子名称: DIHYDROFOLATE REDUCTASE, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: dihydrofolate reductase, structure-based inhibitor design, folateanalogs, rossmann fold, nicotinamide adenine dinucleotide, tuberculosis, oxidoreductase
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18866.88

構造登録者

Li, R.,Sirawaraporn, R.,Chitnumsub, P.,Sirawaraporn, W.,Wooden, J.,Athappilly, F.,Turley, S.,Hol, W.G. (登録日: 1999-11-23, 公開日: 2000-03-09, 最終更新日: 2024-02-07)

主引用文献

Li, R.,Sirawaraporn, R.,Chitnumsub, P.,Sirawaraporn, W.,Wooden, J.,Athappilly, F.,Turley, S.,Hol, W.G.
Three-dimensional structure of M. tuberculosis dihydrofolate reductase reveals opportunities for the design of novel tuberculosis drugs.
J.Mol.Biol., 295:307-323, 2000

PubMed Abstract: Dihydrofolate reductase (DHFR) catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate and is essential for the synthesis of thymidylate, purines and several amino acids. Inhibition of the enzyme's activity leads to arrest of DNA synthesis and cell death. The enzyme has been studied extensively as a drug target for bacterial, protozoal and fungal infections, and also for neoplastic and autoimmune diseases. Here, we report the crystal structure of dihydrofolate reductase from Mycobacterium tuberculosis, a human pathogen responsible for the death of millions of human beings per year. Three crystal structures of ternary complexes of M. tuberculosis DHFR with NADP and different inhibitors have been determined, as well as the binary complex with NADP, with resolutions ranging from 1.7 to 2.0 A. The three DHFR inhibitors are the anticancer drug methotrexate, the antimicrobial trimethoprim and Br-WR99210, an analogue of the antimalarial agent WR99210. Structural comparison of these complexes with human dihydrofolate reductase indicates that the overall protein folds are similar, despite only 26 % sequence identity, but that the environments of both NADP and of the inhibitors contain interesting differences between the enzymes from host and pathogen. Specifically, residues Ala101 and Leu102 near the N6 of NADP are distinctly more hydrophobic in the M. tuberculosis than in the human enzyme. Another striking difference occurs in a region near atoms N1 and N8 of methotrexate, which is also near atom N1 of trimethoprim, and near the N1 and two methyl groups of Br-WR99210. A glycerol molecule binds here in a pocket of the M. tuberculosis DHFR:MTX complex, while this pocket is essentially filled with hydrophobic side-chains in the human enzyme. These differences between the enzymes from pathogen and host provide opportunities for designing new selective inhibitors of M. tuberculosis DHFR.

PubMed: 10623528
DOI: 10.1006/jmbi.1999.3328

実験手法

X-RAY DIFFRACTION (2 Å)