4D41

Crystal structure of S. aureus FabI in complex with NADP and 5-hexyl- 2-(4-nitrophenoxy)phenol

Summary for 4D41

• Entry DOI: 10.2210/pdb4d41/pdb
• Related: 4D42 4D43 4D44 4D45 4D46
• Descriptor: ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADPH], (4S)-2-METHYL-2,4-PENTANEDIOL, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (7 entities in total)
• Functional Keywords: short-chain dehydrogenase/reductase superfamily, fatty acid biosynthesis, lipid synthesis, safabi, fabi, oxidoreductase
• Biological source: STAPHYLOCOCCUS AUREUS
• Total number of polymer chains: 8
• Total formula weight: 259305.11

Authors

Schiebel, J.,Chang, A.,Tonge, P.J.,Sotriffer, C.A.,Kisker, C. (deposition date: 2014-10-26, release date: 2015-03-04, Last modification date: 2023-12-20)

Primary citation

Schiebel, J.,Chang, A.,Merget, B.,Bommineni, G.R.,Yu, W.,Spagnuolo, L.A.,Baxter, M.V.,Tareilus, M.,Tonge, P.J.,Kisker, C.,Sotriffer, C.A.
An Ordered Water Channel in Staphylococcus Aureus Fabi: Unraveling the Mechanism of Substrate Recognition and Reduction.
Biochemistry, 54:1943-, 2015

PubMed Abstract: One third of all drugs in clinical use owe their pharmacological activity to the functional inhibition of enzymes, highlighting the importance of enzymatic targets for drug development. Because of the close relationship between inhibition and catalysis, understanding the recognition and turnover of enzymatic substrates is essential for rational drug design. Although the Staphylococcus aureus enoyl-acyl carrier protein reductase (saFabI) involved in bacterial fatty acid biosynthesis constitutes a very promising target for the development of novel, urgently needed anti-staphylococcal agents, the substrate binding mode and catalytic mechanism remained unclear for this enzyme. Using a combined crystallographic, kinetic, and computational approach, we have explored the chemical properties of the saFabI binding cavity, obtaining a consistent mechanistic model for substrate binding and turnover. We identified a water-molecule network linking the active site with a water basin inside the homo-tetrameric protein, which seems to be crucial for the closure of the flexible substrate binding loop as well as for an effective hydride and proton transfer during catalysis. On the basis of our results, we also derive a new model for the FabI-ACP complex that reveals how the ACP-bound acyl-substrate is injected into the FabI binding crevice. These findings support the future development of novel FabI inhibitors that target the FabI-ACP interface leading to the disruption of the interaction between these two proteins.

PubMed: 25706582
DOI: 10.1021/BI5014358

Experimental method

X-RAY DIFFRACTION (2.3 Å)