6P9T

E.coli LpxA in complex with UDP-3-O-(R-3-hydroxymyristoyl)-GlcNAc and Compound 8

6P9T の概要

• エントリーDOI: 10.2210/pdb6p9t/pdb
• 分子名称: Acyl-[acyl-carrier-protein]--UDP-N-acetylglucosamine O-acyltransferase, uridine-5'-diphosphate-3-O-(R-3-hydroxymyristoyl)-N-acetyl-D-glucosamine, PHOSPHATE ION, ... (6 entities in total)
• 機能のキーワード: acyltransferase, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 30645.85

構造登録者

Ma, X.,Shia, S.,Ornelas, E. (登録日: 2019-06-10, 公開日: 2020-03-11, 最終更新日: 2023-10-11)

主引用文献

Han, W.,Ma, X.,Balibar, C.J.,Baxter Rath, C.M.,Benton, B.,Bermingham, A.,Casey, F.,Chie-Leon, B.,Cho, M.K.,Frank, A.O.,Frommlet, A.,Ho, C.M.,Lee, P.S.,Li, M.,Lingel, A.,Ma, S.,Merritt, H.,Ornelas, E.,De Pascale, G.,Prathapam, R.,Prosen, K.R.,Rasper, D.,Ruzin, A.,Sawyer, W.S.,Shaul, J.,Shen, X.,Shia, S.,Steffek, M.,Subramanian, S.,Vo, J.,Wang, F.,Wartchow, C.,Uehara, T.
Two Distinct Mechanisms of Inhibition of LpxA Acyltransferase Essential for Lipopolysaccharide Biosynthesis.
J.Am.Chem.Soc., 142:4445-4455, 2020

PubMed Abstract: The lipopolysaccharide biosynthesis pathway is considered an attractive drug target against the rising threat of multi-drug-resistant Gram-negative bacteria. Here, we report two novel small-molecule inhibitors (compounds and ) of the acyltransferase LpxA, the first enzyme in the lipopolysaccharide biosynthesis pathway. We show genetically that the antibacterial activities of the compounds against efflux-deficient are mediated by LpxA inhibition. Consistently, the compounds inhibited the LpxA enzymatic reaction in vitro. Intriguingly, using biochemical, biophysical, and structural characterization, we reveal two distinct mechanisms of LpxA inhibition; compound is a substrate-competitive inhibitor targeting apo LpxA, and compound is an uncompetitive inhibitor targeting the LpxA/product complex. Compound exhibited more favorable biological and physicochemical properties than compound and was optimized using structural information to achieve improved antibacterial activity against wild-type . These results show that LpxA is a promising antibacterial target and imply the advantages of targeting enzyme/product complexes in drug discovery.

PubMed: 32064871
DOI: 10.1021/jacs.9b13530

実験手法

X-RAY DIFFRACTION (1.75 Å)