4OXK

Multiple binding modes of inhibitor PT155 to the Mycobacterium tuberculosis enoyl-ACP reductase InhA within a tetramer

4OXK の概要

• エントリーDOI: 10.2210/pdb4oxk/pdb
• 分子名称: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 5-(4-amino-2-methylphenoxy)-2-hexyl-4-hydroxy-1-methylpyridinium, ... (5 entities in total)
• 機能のキーワード: bacterial fatty acid biosynthesis, conformational profile of enzyme-inhibitor complex, inhibition kinetics, substrate-binding loop refolding, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 127374.66

構造登録者

Li, H.J.,Pan, P.,Lai, C.T.,Liu, N.,Garcia-Diaz, M.,Simmerling, C.,Tonge, P.J. (登録日: 2014-02-05, 公開日: 2014-04-30, 最終更新日: 2023-09-27)

主引用文献

Li, H.J.,Lai, C.T.,Pan, P.,Yu, W.,Liu, N.,Bommineni, G.R.,Garcia-Diaz, M.,Simmerling, C.,Tonge, P.J.
A Structural and Energetic Model for the Slow-Onset Inhibition of the Mycobacterium tuberculosis Enoyl-ACP Reductase InhA.
Acs Chem.Biol., 9:986-993, 2014

PubMed Abstract: Slow-onset enzyme inhibitors are of great interest for drug discovery programs since the slow dissociation of the inhibitor from the drug-target complex results in sustained target occupancy leading to improved pharmacodynamics. However, the structural basis for slow-onset inhibition is often not fully understood, hindering the development of structure-kinetic relationships and the rational optimization of drug-target residence time. Previously we demonstrated that slow-onset inhibition of the Mycobacterium tuberculosis enoyl-ACP reductase InhA correlated with motions of a substrate-binding loop (SBL) near the active site. In the present work, X-ray crystallography and molecular dynamics simulations have been used to map the structural and energetic changes of the SBL that occur upon enzyme inhibition. Helix-6 within the SBL adopts an open conformation when the inhibitor structure or binding kinetics is substrate-like. In contrast, slow-onset inhibition results in large-scale local refolding in which helix-6 adopts a closed conformation not normally populated during substrate turnover. The open and closed conformations of helix-6 are hypothesized to represent the EI and EI* states on the two-step induced-fit reaction coordinate for enzyme inhibition. These two states were used as the end points for nudged elastic band molecular dynamics simulations resulting in two-dimensional potential energy profiles that reveal the barrier between EI and EI*, thus rationalizing the binding kinetics observed with different inhibitors. Our findings indicate that the structural basis for slow-onset kinetics can be understood once the structures of both EI and EI* have been identified, thus providing a starting point for the rational control of enzyme-inhibitor binding kinetics.

PubMed: 24527857
DOI: 10.1021/cb400896g

実験手法

X-RAY DIFFRACTION (1.8429 Å)