Structural and mechanistic insights into ligand binding in P2X7 receptors. (360G-Wellcome-099758_Z_12_Z)

£150,048

The human P2X7 receptor (hP2X7R) is a ligand-gated cationic channel which plays a key role in mediating a number of diverse physiological functions induced by extracellular ATP. Alteration in receptor expression and/or function is linked to pathologies including chronic pain, rheumatoid arthritis, neurodegenerative diseases and cancers, which has made the P2X7R anattractive therapeutic target to the pharmaceutical industry. A thorough understanding of the P2X7R structure-function relationship is therefore increasingly crucial to develop P2X7R ligands as therapeutics. This project aims to: 1. Produce models of the P2X7R from different species and use these models andligand docking to map ligand-receptor interactions. These models will then be used to identify a subset of residues within the hP2X7R which are key for ligand-receptor interactions. 2. Investigate the role of key residues identified from modelling and docking by combining site-directed mutagenesis and patch-clamp recording to gain insights into interactions of ATP and antagonist with the hP2X7R. 3. Determine the conformational changes in the hP2X7R between the closed and ATP-bound open states and antagonist-receptor interactions using electron microscopy. These studies will enable us to build a structural and mechanistic understanding of the hP2X7R to facilitate development of therapeutic compoundsand understanding of disease mechanisms.

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Grant Details

Amount Awarded 150048
Applicant Surname Caseley
Approval Committee PhD Studentships
Award Date 2012-06-25T00:00:00+00:00
Financial Year 2011/12
Grant Programme: Title PhD Studentship (Basic)
Internal ID 099758/Z/12/Z
Lead Applicant Ms Emily Caseley
Partnership Value 150048
Planned Dates: End Date 2016-09-30T00:00:00+00:00
Planned Dates: Start Date 2012-10-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Yorkshire and the Humber
Sponsor(s) Prof Alan Berry