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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- natural sciences biological sciences microbiology bacteriology
- natural sciences earth and related environmental sciences geology mineralogy crystallography
- natural sciences physical sciences optics microscopy
- natural sciences biological sciences biochemistry biomolecules lipids
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2014
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
LS2 9JT Leeds
United Kingdom
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.