4OXY
Substrate-binding loop movement with inhibitor PT10 in the tetrameric Mycobacterium tuberculosis enoyl-ACP reductase InhA
Summary for 4OXY
Entry DOI | 10.2210/pdb4oxy/pdb |
Related | 2B36 2X23 4OHU 4OXK 4OXN |
Descriptor | Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 5-hexyl-2-(2-nitrophenoxy)phenol, ... (4 entities in total) |
Functional Keywords | bacterial fatty acid biosynthesis, enzyme-inhibitor complex, substrate-binding loop refolding, conformational heterogeneity, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
Biological source | Mycobacterium tuberculosis |
Total number of polymer chains | 4 |
Total formula weight | 126819.68 |
Authors | Li, H.J.,Sullivan, T.J.,Pan, P.,Lai, C.T.,Liu, N.,Garcia-Diaz, M.,Simmerling, C.,Tonge, P.J. (deposition date: 2014-02-09, 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 Cited by 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: 24527857DOI: 10.1021/cb400896g PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.3501 Å) |
Structure validation
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