4Q9N

Crystal structure of Chlamydia trachomatis enoyl-ACP reductase (FabI) in complex with NADH and AFN-1252

Summary for 4Q9N

• Entry DOI: 10.2210/pdb4q9n/pdb
• Descriptor: Enoyl-[acyl-carrier-protein] reductase [NADH], 1,4-DIHYDRONICOTINAMIDE 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: enoyl-acp reductase, nadh, afn-1252, fatty acid synthesis, chlamydia, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Chlamydia trachomatis F/11-96
• Total number of polymer chains: 8
• Total formula weight: 264267.34

Authors

Yao, J.,Abdelrahman, Y.,Robertson, R.M.,Cox, J.V.,Belland, R.J.,White, S.W.,Rock, C.O. (deposition date: 2014-05-01, release date: 2014-06-25, Last modification date: 2023-09-20)

Primary citation

Yao, J.,Abdelrahman, Y.M.,Robertson, R.M.,Cox, J.V.,Belland, R.J.,White, S.W.,Rock, C.O.
Type II Fatty Acid Synthesis Is Essential for the Replication of Chlamydia trachomatis.
J.Biol.Chem., 289:22365-22376, 2014

PubMed Abstract: The major phospholipid classes of the obligate intracellular bacterial parasite Chlamydia trachomatis are the same as its eukaryotic host except that they also contain chlamydia-made branched-chain fatty acids in the 2-position. Genomic analysis predicts that C. trachomatis is capable of type II fatty acid synthesis (FASII). AFN-1252 was deployed as a chemical tool to specifically inhibit the enoyl-acyl carrier protein reductase (FabI) of C. trachomatis to determine whether chlamydial FASII is essential for replication within the host. The C. trachomatis FabI (CtFabI) is a homotetramer and exhibited typical FabI kinetics, and its expression complemented an Escherichia coli fabI(Ts) strain. AFN-1252 inhibited CtFabI by binding to the FabI·NADH complex with an IC50 of 0.9 μM at saturating substrate concentration. The x-ray crystal structure of the CtFabI·NADH·AFN-1252 ternary complex revealed the specific interactions between the drug, protein, and cofactor within the substrate binding site. AFN-1252 treatment of C. trachomatis-infected HeLa cells at any point in the infectious cycle caused a decrease in infectious titers that correlated with a decrease in branched-chain fatty acid biosynthesis. AFN-1252 treatment at the time of infection prevented the first cell division of C. trachomatis, although the cell morphology suggested differentiation into a metabolically active reticulate body. These results demonstrate that FASII activity is essential for C. trachomatis proliferation within its eukaryotic host and validate CtFabI as a therapeutic target against C. trachomatis.

PubMed: 24958721
DOI: 10.1074/jbc.M114.584185

Experimental method

X-RAY DIFFRACTION (1.795 Å)