Structural basis for dual-mode inhibition of the ABC transporter MsbA.

Autor: Ho H; Structural Biology, Genentech Inc., San Francisco, CA, USA., Miu A; Biochemical and Cellular Pharmacology, Genentech Inc., San Francisco, CA, USA., Alexander MK; Infectious Diseases, Genentech Inc., San Francisco, CA, USA., Garcia NK; Protein Analytical Chemistry, Genentech Inc., San Francisco, CA, USA., Oh A; Structural Biology, Genentech Inc., San Francisco, CA, USA., Zilberleyb I; Biomolecular Resources, Genentech Inc., San Francisco, CA, USA., Reichelt M; Pathology, Genentech Inc., San Francisco, CA, USA., Austin CD; Pathology, Genentech Inc., San Francisco, CA, USA., Tam C; Biomolecular Resources, Genentech Inc., San Francisco, CA, USA., Shriver S; Biomolecular Resources, Genentech Inc., San Francisco, CA, USA., Hu H; Discovery Chemistry, Genentech Inc., San Francisco, CA, USA., Labadie SS; Discovery Chemistry, Genentech Inc., San Francisco, CA, USA., Liang J; Discovery Chemistry, Genentech Inc., San Francisco, CA, USA., Wang L; Discovery Chemistry, Genentech Inc., San Francisco, CA, USA., Wang J; WuXi Apptec. Co. Ltd., Shanghai, China., Lu Y; WuXi Apptec. Co. Ltd., Shanghai, China., Purkey HE; Discovery Chemistry, Genentech Inc., San Francisco, CA, USA., Quinn J; Biochemical and Cellular Pharmacology, Genentech Inc., San Francisco, CA, USA., Franke Y; Biomolecular Resources, Genentech Inc., San Francisco, CA, USA., Clark K; Biochemical and Cellular Pharmacology, Genentech Inc., San Francisco, CA, USA., Beresini MH; Biochemical and Cellular Pharmacology, Genentech Inc., San Francisco, CA, USA., Tan MW; Infectious Diseases, Genentech Inc., San Francisco, CA, USA., Sellers BD; Discovery Chemistry, Genentech Inc., San Francisco, CA, USA., Maurer T; Structural Biology, Genentech Inc., San Francisco, CA, USA., Koehler MFT; Discovery Chemistry, Genentech Inc., San Francisco, CA, USA., Wecksler AT; Protein Analytical Chemistry, Genentech Inc., San Francisco, CA, USA., Kiefer JR; Structural Biology, Genentech Inc., San Francisco, CA, USA., Verma V; Discovery Chemistry, Genentech Inc., San Francisco, CA, USA., Xu Y; Biochemical and Cellular Pharmacology, Genentech Inc., San Francisco, CA, USA., Nishiyama M; Infectious Diseases, Genentech Inc., San Francisco, CA, USA., Payandeh J; Structural Biology, Genentech Inc., San Francisco, CA, USA. payandeh.jian@gene.com.; Infectious Diseases, Genentech Inc., San Francisco, CA, USA. payandeh.jian@gene.com., Koth CM; Structural Biology, Genentech Inc., San Francisco, CA, USA. koth.christopher@gene.com.; Infectious Diseases, Genentech Inc., San Francisco, CA, USA. koth.christopher@gene.com.
Jazyk: angličtina
Zdroj: Nature [Nature] 2018 May; Vol. 557 (7704), pp. 196-201. Date of Electronic Publication: 2018 May 02.
DOI: 10.1038/s41586-018-0083-5
Abstrakt: 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.
Databáze: MEDLINE
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