PXD041359-2

PXD041359 is an original dataset announced via ProteomeXchange.

Title	Conformational restriction shapes the inhibition of a multidrug efflux adaptor protein
Description	Membrane efflux pumps play a major role in bacterial multidrug resistance. The tripartite multidrug efflux pump system from Escherichia coli, AcrAB-TolC, is a target for inhibition to lessen resistance development and restore antibiotic efficacy, with homologs in other ESKAPE pathogens. Here, we rationalize a mechanism of inhibition against the periplasmic adaptor protein, AcrA, using a combination of hydrogen/deuterium exchange mass spectrometry, cellular efflux assays, and molecular dynamics simulations. We define the structural dynamics of AcrA and find that an inhibitor can inflict long-range stabilisation across all four of its domains, whereas an interacting efflux substrate has minimal effect. Our results support a model where an inhibitor forms a molecular wedge within a cleft between the lipoyl and αβ domains of AcrA, diminishing its conformational transmission of drug-evoked signals from AcrB to TolC. This work provides molecular insights into multidrug adaptor protein function which could be valuable for developing antimicrobial therapeutics.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:46:11.819.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Benjamin Russell Lewis
SpeciesList	scientific name: Escherichia coli; NCBI TaxID: 562;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF; SYNAPT G2-Si; Xevo G2-XS QTof

Revision	Datetime	Status	ChangeLog Entry
0	2023-04-05 15:12:47	ID requested
1	2023-06-01 07:07:46	announced
⏵ 2	2024-10-22 05:46:12	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: Membrane proteins,Multidrug efflux pump, Efflux pump inhibitors, HDX-MS

Eamonn Reading
contact affiliation	Department of Chemisty, Redaing Group, King's College London
contact email	eamonn.reading@kcl.ac.uk
lab head
Benjamin Russell Lewis
contact affiliation	King's College London
contact email	benjamin.russell_lewis@kcl.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD041359
     1. Label: PRIDE project
     2. Name: Conformational restriction shapes the inhibition of a multidrug efflux adaptor protein