4OYR

Competition of the small inhibitor PT91 with large fatty acyl substrate of the Mycobacterium tuberculosis enoyl-ACP reductase InhA by induced substrate-binding loop refolding

Summary for 4OYR

• Entry DOI: 10.2210/pdb4oyr/pdb
• Descriptor: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 2-(2-chloranylphenoxy)-5-hexyl-phenol, ... (4 entities in total)
• Functional Keywords: bacterial fatty acid biosynthesis, enzyme-inhibitor complex, substrate-binding loop refolding, induced-fit, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 4
• Total formula weight: 126777.47

Authors

Li, H.J.,Pan, P.,Lai, C.T.,Liu, N.,Garcia-Diaz, M.,Simmerling, C.,Tonge, P.J. (deposition date: 2014-02-13, release date: 2014-04-30, Last modification date: 2023-09-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.2995 Å)