1P45

Targeting tuberculosis and malaria through inhibition of enoyl reductase: compound activity and structural data

1P45 の概要

• エントリーDOI: 10.2210/pdb1p45/pdb
• 関連するPDBエントリー: 1P44
• 分子名称: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, TRICLOSAN, ... (4 entities in total)
• 機能のキーワード: inha, short chain dehydrogenase reductase, triclosan, rossmann fold, enoyl-acp reductase, structural genomics, psi, protein structure initiative, tb structural genomics consortium, tbsgc, oxidoreductase
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 59305.04

構造登録者

Kuo, M.R.,Morbidoni, H.R.,Alland, D.,Sneddon, S.F.,Gourlie, B.B.,Staveski, M.M.,Leonard, M.,Gregory, J.S.,Janjigian, A.D.,Yee, C.,Musser, J.M.,Kreiswirth, B.N.,Iwamoto, H.,Perozzo, R.,Jacobs Jr., W.R.,Sacchettini, J.C.,Fidock, D.A.,TB Structural Genomics Consortium (TBSGC) (登録日: 2003-04-21, 公開日: 2003-09-16, 最終更新日: 2024-12-25)

主引用文献

Kuo, M.R.,Morbidoni, H.R.,Alland, D.,Sneddon, S.F.,Gourlie, B.B.,Staveski, M.M.,Leonard, M.,Gregory, J.S.,Janjigian, A.D.,Yee, C.,Musser, J.M.,Kreiswirth, B.,Iwamoto, H.,Perozzo, R.,Jacobs, W.R.,Sacchettini, J.C.,Fidock, D.A.
Targeting tuberculosis and malaria through inhibition of Enoyl reductase: compound activity and structural data.
J.Biol.Chem., 278:20851-20859, 2003

PubMed Abstract: Tuberculosis and malaria together result in an estimated 5 million deaths annually. The spread of multidrug resistance in the most pathogenic causative agents, Mycobacterium tuberculosis and Plasmodium falciparum, underscores the need to identify active compounds with novel inhibitory properties. Although genetically unrelated, both organisms use a type II fatty-acid synthase system. Enoyl acyl carrier protein reductase (ENR), a key type II enzyme, has been repeatedly validated as an effective antimicrobial target. Using high throughput inhibitor screens with a combinatorial library, we have identified two novel classes of compounds with activity against the M. tuberculosis and P. falciparum enzyme (referred to as InhA and PfENR, respectively). The crystal structure of InhA complexed with NAD+ and one of the inhibitors was determined to elucidate the mode of binding. Structural analysis of InhA with the broad spectrum antimicrobial triclosan revealed a unique stoichiometry where the enzyme contained either a single triclosan molecule, in a configuration typical of other bacterial ENR:triclosan structures, or harbored two triclosan molecules bound to the active site. Significantly, these compounds do not require activation and are effective against wild-type and drug-resistant strains of M. tuberculosis and P. falciparum. Moreover, they provide broader chemical diversity and elucidate key elements of inhibitor binding to InhA for subsequent chemical optimization.

PubMed: 12606558
DOI: 10.1074/jbc.M211968200

実験手法

X-RAY DIFFRACTION (2.6 Å)