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BactoDrug

The Bacteroides dual-pumping membrane-integral pyrophosphatase: a novel drug target

Total Cost €

0

EC-Contrib. €

0

Partnership

0

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 BactoDrug project word cloud

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

gut    internal    function    bacterial    mechanics    guide    conformation    conformational    structure    formed    pyrophosphatase    pore    single    though    transfer    na    dual    mutational    ray    regarding    outstanding    ion    small    ions    thermotoga    abscess    generate    total    utilizing    species    movement    energy    relation    residues    pumping    possess    integral    opened    molecule    healthy    candidates    resonance    maritima    human    despite    couple    plugged    fluorescence    modeling    bacteria    trap    ppases    technologies    rate    collapse    ppase    simulate    perspectives    date    radiata    mortality    stressors    convert    microscopy    anaerobic    resistance    select    pathogenesis    vigna    reflection    infections    pyrophosphatases    questions    career    form    cleavage    escape    gate    molecular    vulgatus    rates    channel    pursuing    membrane    bacteroides    play    closed    structures    kinetics    19    solved    bacteremia    flora    charged    molecules    drug    antibiotic    crystallography    explore   

Project "BactoDrug" data sheet

The following table provides information about the project.

Coordinator
UNIVERSITY OF LEEDS 

Organization address
address: WOODHOUSE LANE
city: LEEDS
postcode: LS2 9JT
website: www.leeds.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]
 Project website http://www.astbury.leeds.ac.uk/people/staff/staffpage.php
 Total cost 183˙454 €
 EC max contribution 183˙454 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2014
 Funding Scheme MSCA-IF-EF-ST
 Starting year 2015
 Duration (year-month-day) from 2015-06-01   to  2017-05-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    UNIVERSITY OF LEEDS UK (LEEDS) coordinator 183˙454.00

Map

 Project objective

Membrane-integral pyrophosphatases (M-PPases) couple cleavage of pyrophosphatase to pumping of ions across a membrane to generate membrane potential and play an important role in resistance to stressors. The solved structures of an H-pumping M-PPase from Vigna radiata and an Na-pumping M-PPase from Thermotoga maritima show M-PPases form a channel through the membrane, and this channel is plugged by an ion gate formed by three charged residues. Despite these structures, there are still many outstanding questions regarding M-PPases, especially in relation to H and Na dual-pumping M-PPases.

Bacteroides species are a major cause of anaerobic infections, and though they are part of a healthy human gut flora, when these bacteria escape the gut, they can cause bacteremia and abscess formation. Bacteroides species are associated with high antibiotic resistance rates and have a 19% or greater mortality rate. However, they do possess a possible drug target: an H/Na-pumping M-PPase.

A major goal of this project is to solve the structure of the Bacteroides vulgatus H/Na-pumping M-PPase to guide mutational studies to determine how M-PPases select for ions and to explore how the ion gate is opened and closed during ion pumping. Since the ion gate is closed in all M-PPase structures to date, I will also use single molecule fluorescence resonance energy transfer and total internal reflection fluorescence microscopy to determine the kinetics and conformational changes during ion gate movement. Finally, I will use molecular mechanics modeling to simulate ion gate function and design small-molecule drug candidates. Molecules that trap the ion gate in the open conformation will convert M-PPase into a pore in the membrane of Bacteroides species, leading to collapse of the membrane potential.

This project will further my career goal of pursuing research in bacterial pathogenesis from various perspectives, utilizing X-ray crystallography and single molecule technologies.

 Publications

year authors and title journal last update
List of publications.
2017 Shah NR, Wilkinson C, Harborne SP, Turku A, Li KM, Sun YJ, Harris S, Goldman A.
Insights into the mechanism of membrane pyrophosphatases by combining experiment and computer simulation.
published pages: , ISSN: 2329-7778, DOI:
Structural Dynamics 2019-07-24
2016 Nita R. Shah, Keni Vidilaseris, Henri Xhaard, Adrian Goldman
Integral membrane pyrophosphatases: a novel drug target for human pathogens?
published pages: 171-194, ISSN: 2377-9098, DOI: 10.3934/biophy.2016.1.171
AIMS Biophysics 3/1 2019-07-24

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