PDBsum entry 5ugt

Oxidoreductase

PDB id: 5ugt

Contents

Protein chains

268 a.a.

Ligands

NAD ×4

XTW ×4

Waters ×133

PDB id:

5ugt

Name:

Oxidoreductase

Title:

Crystal structure of m. Tuberculosis inha inhibited by pt504

Structure:

Enoyl-[acyl-carrier-protein] reductase [nadh]. Chain: a, b, e, g. Synonym: enoyl-acp reductase,fas-ii enoyl-acp reductase,nadh- dependent 2-trans-enoyl-acp reductase. Engineered: yes

Source:

Mycobacterium tuberculosis. Organism_taxid: 1773. Gene: inha, rv1484, mtcy277.05. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.60Å R-factor: 0.212 R-free: 0.239

Authors:

S.Eltschkner,A.Pschibul,L.A.Spagnuolo,W.Yu,P.J.Tonge,C.Kisker

Key ref:

L.A.Spagnuolo et al. (2017). Evaluating the Contribution of Transition-State Destabilization to Changes in the Residence Time of Triazole-Based InhA Inhibitors. J Am Chem Soc, 139, 3417-3429. PubMed id: 28151657 DOI: 10.1021/jacs.6b11148

Date:

10-Jan-17 Release date: 15-Feb-17

Protein chains

P9WGR1  (INHA_MYCTU) -  Enoyl-[acyl-carrier-protein] reductase [NADH] from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)

Seq: 269 a.a.

Struc: 268 a.a.

Enzyme reactions

• Enzyme class: E.C.1.3.1.9 - enoyl-[acyl-carrier-protein] reductase (NADH).
• Reaction: a 2,3-saturated acyl-[ACP] + NAD⁺ = a (2E)-enoyl-[ACP] + NADH + H⁺

2,3-saturated acyl-[ACP] + NAD(+) (Bound ligand (Het Group name = NAD) corresponds exactly) = (2E)-enoyl-[ACP] + NADH + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/jacs.6b11148

J Am Chem Soc 139:3417-3429 (2017)

PubMed id: 28151657

Evaluating the Contribution of Transition-State Destabilization to Changes in the Residence Time of Triazole-Based InhA Inhibitors.

L.A.Spagnuolo, S.Eltschkner, W.Yu, F.Daryaee, S.Davoodi, S.E.Knudson, E.K.Allen, J.Merino, A.Pschibul, B.Moree, N.Thivalapill, J.J.Truglio, J.Salafsky, R.A.Slayden, C.Kisker, P.J.Tonge.

ABSTRACT

A critical goal of lead compound selection and optimization is to maximize target engagement while minimizing off-target binding. Since target engagement is a function of both the thermodynamics and kinetics of drug-target interactions, it follows that the structures of both the ground states and transition states on the binding reaction coordinate are needed to rationally modulate the lifetime of the drug-target complex. Previously, we predicted the structure of the rate-limiting transition state that controlled the time-dependent inhibition of the enoyl-ACP reductase InhA. This led to the discovery of a triazole-containing diphenyl ether with an increased residence time on InhA due to transition-state destabilization rather than ground-state stabilization. In the present work, we evaluate the inhibition of InhA by 14 triazole-based diphenyl ethers and use a combination of enzyme kinetics and X-ray crystallography to generate a structure-kinetic relationship for time-dependent binding. We show that the triazole motif slows the rate of formation for the final drug-target complex by up to 3 orders of magnitude. In addition, we identify a novel inhibitor with a residence time on InhA of 220 min, which is 3.5-fold longer than that of the INH-NAD adduct formed by the tuberculosis drug, isoniazid. This study provides a clear example in which the lifetime of the drug-target complex is controlled by interactions in the transition state for inhibitor binding rather than the ground state of the enzyme-inhibitor complex, and demonstrates the important role that on-rates can play in drug-target residence time.