6YUR

Crystal structure of S. aureus FabI inhibited by SKTS1

Summary for 6YUR

• Entry DOI: 10.2210/pdb6yur/pdb
• Descriptor: Enoyl-[acyl-carrier-protein] reductase [NADPH], NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 6-[4-(4-hexyl-2-oxidanyl-phenoxy)phenoxy]pyridin-2-ol, ... (4 entities in total)
• Functional Keywords: bacterial enoyl-acp reductase, diphenylether, residence time, oxidoreductase
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 8
• Total formula weight: 258136.75

Authors

Weinrich, J.D.,Eltschkner, S.,Schiebel, J.,Kehrein, J.,Le, T.A.,Davoodi, S.,Merget, B.,Tonge, P.J.,Engels, B.,Sotriffer, C.A.,Kisker, C. (deposition date: 2020-04-27, release date: 2021-03-24, Last modification date: 2024-01-24)

Primary citation

Eltschkner, S.,Kehrein, J.,Le, T.A.,Davoodi, S.,Merget, B.,Basak, S.,Weinrich, J.D.,Schiebel, J.,Tonge, P.J.,Engels, B.,Sotriffer, C.,Kisker, C.
A Long Residence Time Enoyl-Reductase Inhibitor Explores an Extended Binding Region with Isoenzyme-Dependent Tautomer Adaptation and Differential Substrate-Binding Loop Closure.
Acs Infect Dis., 7:746-758, 2021

PubMed Abstract: The enoyl-acyl carrier protein (ACP) reductase (ENR) is a key enzyme within the bacterial fatty-acid synthesis pathway. It has been demonstrated that small-molecule inhibitors carrying the diphenylether (DPE) scaffold bear a great potential for the development of highly specific and effective drugs against this enzyme class. Interestingly, different substitution patterns of the DPE scaffold have been shown to lead to varying effects on the kinetic and thermodynamic behavior toward ENRs from different organisms. Here, we investigated the effect of a 4'-pyridone substituent in the context of the slow tight-binding inhibitor SKTS1 on the inhibition of the enoyl-ACP-reductase saFabI and the closely related isoenzyme from , InhA, and explored a new interaction site of DPE inhibitors within the substrate-binding pocket. Using high-resolution crystal structures of both complexes in combination with molecular dynamics (MD) simulations, kinetic measurements, and quantum mechanical (QM) calculations, we provide evidence that the 4'-pyridone substituent adopts different tautomeric forms when bound to the two ENRs. We furthermore elucidate the structural determinants leading to significant differences in the residence time of SKTS1 on both enzymes.

PubMed: 33710875
DOI: 10.1021/acsinfecdis.0c00437

Experimental method

X-RAY DIFFRACTION (1.96 Å)