6AHE

Crystal structure of enoyl-ACP reductase from Acinetobacter baumannii in complex with NAD and AFN-1252

Summary for 6AHE

• Entry DOI: 10.2210/pdb6ahe/pdb
• Descriptor: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, N-methyl-N-[(3-methyl-1-benzofuran-2-yl)methyl]-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)propanamide, ... (4 entities in total)
• Functional Keywords: fabi, acinetobacter baumannii, nad, afn-1252, inhibitor complex, oxidoreductase
• Biological source: Acinetobacter baumannii ATCC 19606 = CIP 70.34 = JCM 6841 (Acinetobacter baumannii ATCC 19606)
• Total number of polymer chains: 4
• Total formula weight: 118806.43

Authors

Rani, S.T.,Nataraj, V.,Laxminarasimhan, A.,Thomas, A.,Krishnamurthy, N. (deposition date: 2018-08-17, release date: 2019-08-21, Last modification date: 2023-11-22)

Primary citation

Rao, N.K.,Nataraj, V.,Ravi, M.,Panchariya, L.,Palai, K.,Talapati, S.R.,Lakshminarasimhan, A.,Ramachandra, M.,Antony, T.
Ternary complex formation of AFN-1252 with Acinetobacter baumannii FabI and NADH: Crystallographic and biochemical studies.
Chem.Biol.Drug Des., 96:704-713, 2020

PubMed Abstract: Acinetobacter baumannii is an opportunistic Gram-negative bacterial pathogen, associated mostly with hospital-acquired infections. The emergence of drug resistance strains made it necessary to explore new pathways for the development of more effective antibiotics. Enoyl CoA reductase (FabI), a key enzyme in the fatty acid biosynthesis (FAS) pathway, has emerged as a potential target for antibacterial drug development. Earlier reports show that the lead SaFabI inhibitor AFN-1252 can inhibit FabI from other organisms including Escherichia coli and Burkholderia pseudomallei, but with differential potency. In the present work, we show that AFN-1252 is a moderate inhibitor of AbFabI with an IC of 216 nM. AFN-1252 stabilized AbFabI with a 4.2°C increase in the melting temperature (T ) and, interestingly, the stabilization effect was significantly increased in presence of the cofactor NADH (∆T  = 17°C), suggesting the formation of a ternary complex AbFabI: AFN-1252: NADH. X-ray crystallography studies of AbFabI co-crystalized with AFN-1252 and NADH confirmed the ternary complex formation. The critical interactions of AFN-1252 with AbFabI and NADH identified from the co-crystal structure may facilitate the design and development of new drugs against A. baumannii infections by targeting the FAS pathway.

PubMed: 32227402
DOI: 10.1111/cbdd.13686

Experimental method

X-RAY DIFFRACTION (2.29 Å)