Understanding the Molecular Mechanisms of P2X7 Receptor Signal Transduction
EMSL Project ID
50744
Abstract
P2X receptors are trimeric, non-selective cation channels activated by extracellular ATP to modulate processes in the cardiovascular and immune systems. P2X7 receptor, the most structurally and functionally distinct P2X receptor subtype, is involved in signaling pathways for apoptosis and inflammation, and is predicted to play a key role in the link between inflammatory diseases and the development of atherosclerosis. Many of P2X7 receptor’s unique functional properties are thought to occur through its cytoplasmic domain. But, because there is currently no published structural information on this part of the receptor, the molecular principles governing P2X7 receptor pharmacology and signal transduction are not known, slowing the development of small molecules that can inhibit receptor function. However, my group has recently determined the first atomic resolution cryo electron microscopy structures of full-length P2X7 receptor in both apo (2.9 Å) and open (3.3 Å) states. This is important because all previous structures of this receptor family used truncated constructs, some of which resulted in structural distortion. Moreover, our work provides the first structure of a P2X cytoplasmic domain, found to contain a novel protein fold previously undescribed in the PDB, and explains why the P2X7 receptor does not undergo desensitization, revealing a unique structural role by which palmitoyl groups modulate receptor function. Finally, and most surprisingly, our cryo EM structures reveal a dinuclear zinc ion complex and a high-affinity guanosine nucleotide-binding site in the cytoplasmic domain, the latter of which might be involved in P2X7’s ability to recruit protein kinases. The major aim of this proposal is to use cryo electron microscopy to fully understand the structural conformations governing P2X7 receptor function, especially as it relates to the guanine-nucleotide/receptor interaction. Our explicit aim is toward the development of small molecule inhibitors that modulate P2X7 function and signal transduction. Identification of small molecules that successfully inhibit P2X7 receptor activation or modulate P2X7 receptor intracellular signaling pathways can potentially be used to treat vascular inflammation and prevent atherosclerosis.
Project Details
Start Date
2019-04-15
End Date
2021-03-17
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members