4BNK

Crystal structure of S. aureus FabI in complex with NADP and 5-fluoro- 2-phenoxyphenol

Summary for 4BNK

• Entry DOI: 10.2210/pdb4bnk/pdb
• Related: 4BNF 4BNG 4BNH 4BNI 4BNJ 4BNL 4BNM 4BNN
• Descriptor: ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADPH], NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 5-fluoro-2-phenoxyphenol, ... (6 entities in total)
• Functional Keywords: oxidoreductase, short-chain dehydrogenase/reductase superfamily, fatty acid biosynthesis, lipid synthesis, safabi
• Biological source: STAPHYLOCOCCUS AUREUS SUBSP. AUREUS
• Total number of polymer chains: 8
• Total formula weight: 257505.83

Authors

Schiebel, J.,Chang, A.,Bommineni, G.R.,Tonge, P.J.,Kisker, C. (deposition date: 2013-05-15, release date: 2013-06-05, Last modification date: 2023-12-20)

Primary citation

Chang, A.,Schiebel, J.,Yu, W.,Bommineni, G.R.,Pan, P.,Baxter, M.V.,Khanna, A.,Sotriffer, C.A.,Kisker, C.F.,Tonge, P.J.
Rational Optimization of Drug-Target Residence Time: Insights from Inhibitor Binding to the S. Aureus Fabi Enzyme-Product Complex.
Biochemistry, 52:4217-, 2013

PubMed Abstract: Drug-target kinetics has recently emerged as an especially important facet of the drug discovery process. In particular, prolonged drug-target residence times may confer enhanced efficacy and selectivity in the open in vivo system. However, the lack of accurate kinetic and structural data for a series of congeneric compounds hinders the rational design of inhibitors with decreased off-rates. Therefore, we chose the Staphylococcus aureus enoyl-ACP reductase (saFabI)--an important target for the development of new anti-staphylococcal drugs--as a model system to rationalize and optimize the drug-target residence time on a structural basis. Using our new, efficient, and widely applicable mechanistically informed kinetic approach, we obtained a full characterization of saFabI inhibition by a series of 20 diphenyl ethers complemented by a collection of 9 saFabI-inhibitor crystal structures. We identified a strong correlation between the affinities of the investigated saFabI diphenyl ether inhibitors and their corresponding residence times, which can be rationalized on a structural basis. Because of its favorable interactions with the enzyme, the residence time of our most potent compound exceeds 10 h. In addition, we found that affinity and residence time in this system can be significantly enhanced by modifications predictable by a careful consideration of catalysis. Our study provides a blueprint for investigating and prolonging drug-target kinetics and may aid in the rational design of long-residence-time inhibitors targeting the essential saFabI enzyme.

PubMed: 23697754
DOI: 10.1021/BI400413C

Experimental method

X-RAY DIFFRACTION (2.5 Å)