3II4

Structure of mycobacterial lipoamide dehydrogenase bound to a triazaspirodimethoxybenzoyl inhibitor

3II4 の概要

• エントリーDOI: 10.2210/pdb3ii4/pdb
• 関連するPDBエントリー: 2A8X
• 分子名称: Dihydrolipoyl dehydrogenase, FLAVIN-ADENINE DINUCLEOTIDE, N-[2-(2,4-dichlorophenyl)ethyl]-2-{8-[(2,4-dimethoxyphenyl)carbonyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl}acetamide, ... (4 entities in total)
• 機能のキーワード: dihydrolipoyl dehydrogenase, dhldh, e3, protein-n6-(dihydrolipoyl)lysine, nad+ oxidoreductase, nad+, nadh, cytoplasm, disulfide bond, fad, flavoprotein, glycolysis, nad, oxidoreductase, redox-active center
• 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: 101696.25

構造登録者

Lima, C.D. (登録日: 2009-07-31, 公開日: 2010-01-26, 最終更新日: 2024-11-20)

主引用文献

Bryk, R.,Arango, N.,Venugopal, A.,Warren, J.D.,Park, Y.H.,Patel, M.S.,Lima, C.D.,Nathan, C.
Triazaspirodimethoxybenzoyls as selective inhibitors of mycobacterial lipoamide dehydrogenase .
Biochemistry, 49:1616-1627, 2010

PubMed Abstract: Mycobacterium tuberculosis (Mtb) remains the leading single cause of death from bacterial infection. Here we explored the possibility of species-selective inhibition of lipoamide dehydrogenase (Lpd), an enzyme central to Mtb's intermediary metabolism and antioxidant defense. High-throughput screening of combinatorial chemical libraries identified triazaspirodimethoxybenzoyls as high-nanomolar inhibitors of Mtb's Lpd that were noncompetitive versus NADH, NAD(+), and lipoamide and >100-fold selective compared to human Lpd. Efficacy required the dimethoxy and dichlorophenyl groups. The structure of an Lpd-inhibitor complex was resolved to 2.42 A by X-ray crystallography, revealing that the inhibitor occupied a pocket adjacent to the Lpd NADH/NAD(+) binding site. The inhibitor did not overlap with the adenosine moiety of NADH/NAD(+) but did overlap with positions predicted to bind the nicotinamide rings in NADH and NAD(+) complexes. The dimethoxy ring occupied a deep pocket adjacent to the FAD flavin ring where it would block coordination of the NADH nicotinamide ring, while the dichlorophenyl group occupied a more exposed pocket predicted to coordinate the NAD(+) nicotinamide. Several residues that are not conserved between the bacterial enzyme and its human homologue were predicted to contribute both to inhibitor binding and to species selectivity, as confirmed for three residues by analysis of the corresponding mutant Mtb Lpd proteins. Thus, nonconservation of residues lining the electron-transfer tunnel in Mtb Lpd can be exploited for development of species-selective Lpd inhibitors.

PubMed: 20078138
DOI: 10.1021/bi9016186

実験手法

X-RAY DIFFRACTION (2.42 Å)