7SEL

E. coli MsbA in complex with LPS and inhibitor G7090 (compound 3)

7SEL の概要

• エントリーDOI: 10.2210/pdb7sel/pdb
• 分子名称: ATP-dependent lipid A-core flippase, (2E)-3-{7-[(1S)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1-methylnaphthalen-2-yl}prop-2-enoic acid, (2~{R},4~{R},5~{R},6~{R})-6-[(1~{R})-1,2-bis(oxidanyl)ethyl]-2-[(2~{R},4~{R},5~{R},6~{R})-6-[(1~{R})-1,2-bis(oxidanyl)ethyl]-2-carboxy-2-[[(2~{R},3~{S},4~{R},5~{R},6~{R})-5-[[(3~{R})-3-dodecanoyloxytetradecanoyl]amino]-6-[[(2~{R},3~{S},4~{R},5~{R},6~{R})-3-oxidanyl-5-[[(3~{R})-3-oxidanyltetradecanoyl]amino]-4-[(3~{R})-3-oxidanyltetradecanoyl]oxy-6-phosphonooxy-oxan-2-yl]methoxy]-3-phosphonooxy-4-[(3~{R})-3-tetradecanoyloxytetradecanoyl]oxy-oxan-2-yl]methoxy]-5-oxidanyl-oxan-4-yl]oxy-4,5-bis(oxidanyl)oxane-2-carboxylic acid (3 entities in total)
• 機能のキーワード: msba, lipid a, lps, inhibitor, lipid transport, translocase
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 136124.37

構造登録者

Payandeh, J.,Koth, C.M.,Verma, V.A. (登録日: 2021-09-30, 公開日: 2022-03-09, 最終更新日: 2024-05-22)

主引用文献

Verma, V.A.,Wang, L.,Labadie, S.S.,Liang, J.,Sellers, B.D.,Wang, J.,Dong, L.,Wang, Q.,Zhang, S.,Xu, Z.,Zhang, Y.,Niu, Y.,Wang, X.,Wai, J.,Koehler, M.F.T.,Hu, H.,Alexander, M.K.,Nishiyama, M.,Miu, A.,Xu, Y.,Pang, J.,Katakam, A.K.,Reichelt, M.,Austin, C.D.,Ho, H.,Payandeh, J.,Koth, C.M.
Discovery of Inhibitors of the Lipopolysaccharide Transporter MsbA: From a Screening Hit to Potent Wild-Type Gram-Negative Activity.
J.Med.Chem., 65:4085-4120, 2022

PubMed Abstract: The dramatic increase in the prevalence of multi-drug resistant Gram-negative bacterial infections and the simultaneous lack of new classes of antibiotics is projected to result in approximately 10 million deaths per year by 2050. We report on efforts to target the Gram-negative ATP-binding cassette (ABC) transporter MsbA, an essential inner membrane protein that transports lipopolysaccharide from the inner leaflet to the periplasmic face of the inner membrane. We demonstrate the improvement of a high throughput screening hit into compounds with on-target single digit micromolar (μM) minimum inhibitory concentrations against wild-type uropathogenic , , and . A 2.98 Å resolution X-ray crystal structure of MsbA complexed with an inhibitor revealed a novel mechanism for inhibition of an ABC transporter. The identification of a fully encapsulated membrane binding site in Gram-negative bacteria led to unique physicochemical property requirements for wild-type activity.

PubMed: 35184554
DOI: 10.1021/acs.jmedchem.1c01909

実験手法

X-RAY DIFFRACTION (2.978 Å)