6TBB
Crystal structure of S. aureus FabI in complex with NADPH and kalimantacin A (batumin)
Summary for 6TBB
| Entry DOI | 10.2210/pdb6tbb/pdb |
| Related | 6TBC |
| Descriptor | Enoyl-[acyl-carrier-protein] reductase [NADPH], NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, Kalimantacin, ... (4 entities in total) |
| Functional Keywords | enoyl-[acyl carrier protein] reductase, fatty acid biosynthesis, rossmann fold, short-chain dehydrogenase/reductase, biosynthetic protein |
| Biological source | Staphylococcus aureus |
| Total number of polymer chains | 8 |
| Total formula weight | 238075.17 |
| Authors | Fage, C.D.,Masschelein, J. (deposition date: 2019-11-01, release date: 2020-04-01, Last modification date: 2024-01-24) |
| Primary citation | Fage, C.D.,Lathouwers, T.,Vanmeert, M.,Gao, L.J.,Vrancken, K.,Lammens, E.M.,Weir, A.N.M.,Degroote, R.,Cuppens, H.,Kosol, S.,Simpson, T.J.,Crump, M.P.,Willis, C.L.,Herdewijn, P.,Lescrinier, E.,Lavigne, R.,Anne, J.,Masschelein, J. The Kalimantacin Polyketide Antibiotics Inhibit Fatty Acid Biosynthesis in Staphylococcus aureus by Targeting the Enoyl-Acyl Carrier Protein Binding Site of FabI. Angew.Chem.Int.Ed.Engl., 59:10549-10556, 2020 Cited by PubMed Abstract: The enoyl-acyl carrier protein reductase enzyme FabI is essential for fatty acid biosynthesis in Staphylococcus aureus and represents a promising target for the development of novel, urgently needed anti-staphylococcal agents. Here, we elucidate the mode of action of the kalimantacin antibiotics, a novel class of FabI inhibitors with clinically-relevant activity against multidrug-resistant S. aureus. By combining X-ray crystallography with molecular dynamics simulations, in vitro kinetic studies and chemical derivatization experiments, we characterize the interaction between the antibiotics and their target, and we demonstrate that the kalimantacins bind in a unique conformation that differs significantly from the binding mode of other known FabI inhibitors. We also investigate mechanisms of acquired resistance in S. aureus and identify key residues in FabI that stabilize the binding of the antibiotics. Our findings provide intriguing insights into the mode of action of a novel class of FabI inhibitors that will inspire future anti-staphylococcal drug development. PubMed: 32208550DOI: 10.1002/anie.201915407 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.45 Å) |
Structure validation
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