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VisTrans SIGNED

Visualising transport dynamics of transmembrane pumps

Total Cost €

0

EC-Contrib. €

0

Partnership

0

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 VisTrans project word cloud

Explore the words cloud of the VisTrans project. It provides you a very rough idea of what is the project "VisTrans" about.

electrochemical    energized    observations    antibiotics    series    structural    mechanism    pump    prepare    indicates    polypeptides    secretion    vitro    regulated    crystallography    drive    look    negative    macrolide    atp    toxins    bacteria    earlier    diverse    cooperative    efflux    constricted    assembly    assembled    peptides    tertiary    assemblies    binding    gradients    cell    resolution    energy    molecular    understand    drug    visualize    regulation    encompassing    stereochemical    mechanistic    vivo    switching    intermediates    virulence    strains    complemented    central    transport    basis    isolation    quaternary    transporters    intermediate    pumps    envelope    capture    translocate    substrate    cycle    cycles    small    description    threading    pathogenic    futile    engineer    modulated    dissipate    toxin    translocation    resistance    questions    hydrolysis    cryoem    machines    conformational    tripartite    structure    cooperativity    gram    channel    protein    play    situ    co    switch    substrates    secondary   

Project "VisTrans" data sheet

The following table provides information about the project.

Coordinator
THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE 

Organization address
address: TRINITY LANE THE OLD SCHOOLS
city: CAMBRIDGE
postcode: CB2 1TN
website: www.cam.ac.uk

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country United Kingdom [UK]
 Total cost 2˙208˙618 €
 EC max contribution 2˙208˙618 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2016-ADG
 Funding Scheme ERC-ADG
 Starting year 2017
 Duration (year-month-day) from 2017-09-01   to  2022-08-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE UK (CAMBRIDGE) coordinator 2˙208˙618.00

Map

 Project objective

The project will investigate multi-component molecular machines that drive substrates across the cell envelope of bacteria. Some of the machines pump antibiotics or toxins, and so contribute to drug resistance and virulence in pathogenic strains. Questions that will be addressed include what the molecular pumps look like, how they are assembled and regulated, how they capture and translocate substrates, and the stereochemical basis for the cooperative switching of substrate-binding states. Molecular pumps that will be studied include tripartite systems driven by ATP hydrolysis, which play a central role in the efflux of macrolide antibiotics and secretion of toxins in Gram-negative bacteria, and those that use secondary transporters energized by electrochemical gradients. We will build upon our earlier observations to prepare a series of intermediates encompassing the key steps in the transport processes, to visualize tertiary and quaternary structural changes, the pathway of substrates in the efflux pumps, and the threading of toxin polypeptides through the constricted channel in the secretion assembly. The pumps and secretion systems cycle through intermediate states, and these will be studied at high resolution by cryoEM and crystallography to understand how the conformational states switch with strong cooperativity and avoid futile cycles that dissipate energy. Our work indicates that the activity of these transporters can be modulated by small peptides and potential co-factors, and we will address how these work. The project will build on our novel approach to engineer the pump assemblies that enables structural analysis at high resolution in isolation and in situ, and will be complemented with mechanistic analyses in vitro and in vivo. The project will deliver a comprehensive, structure-based description of the mechanism of drug efflux and protein translocation by transport machines and their regulation in diverse pathogenic bacteria.

 Publications

year authors and title journal last update
List of publications.
2018 Dijun Du, Xuan Wang-Kan, Arthur Neuberger, Hendrik W. van Veen, Klaas M. Pos, Laura J. V. Piddock, Ben F. Luisi
Multidrug efflux pumps: structure, function and regulation
published pages: 523-539, ISSN: 1740-1526, DOI: 10.1038/s41579-018-0048-6
Nature Reviews Microbiology 16/9 2020-01-28

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