Distinct allosteric mechanisms of first-generation MsbA inhibitors.

Tytuł:: Distinct allosteric mechanisms of first-generation MsbA inhibitors.
Autorzy:: Thélot FA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Biological and Biomedical Sciences Program, Harvard University, Cambridge, MA, USA.
Zhang W; Key Laboratory of Structural Biology of Zhejiang Province, Westlake University, Hangzhou, China.; Westlake AI Therapeutics Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
Song K; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.; Cryo-EM Core Facility, University of Massachusetts Medical School, Worcester, MA, USA.
Xu C; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.; Cryo-EM Core Facility, University of Massachusetts Medical School, Worcester, MA, USA.
Huang J; Key Laboratory of Structural Biology of Zhejiang Province, Westlake University, Hangzhou, China.; Westlake AI Therapeutics Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
Liao M; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Źródło:: Science (New York, N.Y.) [Science] 2021 Oct 29; Vol. 374 (6567), pp. 580-585. Date of Electronic Publication: 2021 Sep 23.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: : Washington, DC : American Association for the Advancement of Science
Original Publication: New York, N.Y. : [s.n.] 1880-
MeSH Terms:: ATP-Binding Cassette Transporters/*antagonists & inhibitors
ATP-Binding Cassette Transporters/*metabolism
Bacterial Proteins/*antagonists & inhibitors
Bacterial Proteins/*metabolism
ATP-Binding Cassette Transporters/chemistry ; Adenosine Triphosphatases/metabolism ; Allosteric Regulation ; Bacterial Proteins/chemistry ; Binding Sites ; Cryoelectron Microscopy ; Drug Discovery ; Imaging, Three-Dimensional ; Lipopolysaccharides/metabolism ; Models, Molecular ; Molecular Dynamics Simulation ; Protein Binding ; Protein Conformation ; Small Molecule Libraries
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Grant Information:: R01 GM122797 United States GM NIGMS NIH HHS
Substance Nomenclature:: 0 (ATP-Binding Cassette Transporters)
0 (Bacterial Proteins)
0 (Lipopolysaccharides)
0 (MsbA protein, Bacteria)
0 (Small Molecule Libraries)
EC 3.6.1.- (Adenosine Triphosphatases)
Entry Date(s):: Date Created: 20210923 Date Completed: 20211115 Latest Revision: 20221030
Update Code:: 20240105
PubMed Central ID:: PMC9109178
DOI:: 10.1126/science.abi9009
PMID:: 34554829
: Czasopismo naukowe

Pełny tekst

ATP-binding cassette (ABC) transporters couple adenosine 5′-triphosphate (ATP) hydrolysis to substrate transport across biological membranes. Although many are promising drug targets, their mechanisms of modulation by small-molecule inhibitors remain largely unknown. Two first-generation inhibitors of the MsbA transporter, tetrahydrobenzothiophene 1 (TBT1) and G247, induce opposite effects on ATP hydrolysis. Using single-particle cryo–electron microscopy and functional assays, we show that TBT1 and G247 bind adjacent yet separate pockets in the MsbA transmembrane domains. Two TBT1 molecules asymmetrically occupy the substrate-binding site, which leads to a collapsed inward-facing conformation with decreased distance between the nucleotide-binding domains (NBDs). By contrast, two G247 molecules symmetrically increase NBD distance in a wide inward-open state of MsbA. The divergent mechanisms of action of these MsbA inhibitors provide important insights into ABC transporter pharmacology.

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