6BPP

E. coli MsbA in complex with LPS and inhibitor G092

Summary for 6BPP

• Entry DOI: 10.2210/pdb6bpp/pdb
• Descriptor: Lipid A export ATP-binding/permease protein MsbA, alpha-D-glucopyranose-(1-3)-[alpha-D-glucopyranose-(1-6)]alpha-D-glucopyranose-(1-3)-[L-glycero-alpha-D-manno-heptopyranose-(1-7)]L-glycero-alpha-D-manno-heptopyranose-(1-3)-L-glycero-alpha-D-manno-heptopyranose-(1-5)-[3-deoxy-alpha-D-manno-oct-2-ulopyranosonic acid-(2-4)]3-deoxy-alpha-D-manno-oct-2-ulopyranosonic acid-(2-6)-2-amino-2-deoxy-beta-D-glucopyranose-(1-6)-2-amino-2-deoxy-alpha-D-glucopyranose, (2E)-3-{6-[(1S)-1-(3-amino-2,6-dichlorophenyl)ethoxy]-4-cyclopropylquinolin-3-yl}prop-2-enoic acid, ... (8 entities in total)
• Functional Keywords: abc transporter, inhibitor, lps, msba, lipid transport
• Biological source: Escherichia coli O6:H1 (strain CFT073 / ATCC 700928 / UPEC)
• Total number of polymer chains: 2
• Total formula weight: 138535.67

Authors

Ho, H.,Koth, C.M.,Payandeh, J. (deposition date: 2017-11-24, release date: 2018-05-02, Last modification date: 2024-03-13)

Primary citation

Ho, H.,Miu, A.,Alexander, M.K.,Garcia, N.K.,Oh, A.,Zilberleyb, I.,Reichelt, M.,Austin, C.D.,Tam, C.,Shriver, S.,Hu, H.,Labadie, S.S.,Liang, J.,Wang, L.,Wang, J.,Lu, Y.,Purkey, H.E.,Quinn, J.,Franke, Y.,Clark, K.,Beresini, M.H.,Tan, M.W.,Sellers, B.D.,Maurer, T.,Koehler, M.F.T.,Wecksler, A.T.,Kiefer, J.R.,Verma, V.,Xu, Y.,Nishiyama, M.,Payandeh, J.,Koth, C.M.
Structural basis for dual-mode inhibition of the ABC transporter MsbA.
Nature, 557:196-201, 2018

PubMed Abstract: The movement of core-lipopolysaccharide across the inner membrane of Gram-negative bacteria is catalysed by an essential ATP-binding cassette transporter, MsbA. Recent structures of MsbA and related transporters have provided insights into the molecular basis of active lipid transport; however, structural information about their pharmacological modulation remains limited. Here we report the 2.9 Å resolution structure of MsbA in complex with G907, a selective small-molecule antagonist with bactericidal activity, revealing an unprecedented mechanism of ABC transporter inhibition. G907 traps MsbA in an inward-facing, lipopolysaccharide-bound conformation by wedging into an architecturally conserved transmembrane pocket. A second allosteric mechanism of antagonism occurs through structural and functional uncoupling of the nucleotide-binding domains. This study establishes a framework for the selective modulation of ABC transporters and provides rational avenues for the design of new antibiotics and other therapeutics targeting this protein family.

PubMed: 29720648
DOI: 10.1038/s41586-018-0083-5

Experimental method

X-RAY DIFFRACTION (2.92 Å)