# Structure/Function Studies on the Mechanisms of Purinergic Receptor Activation and Antagonism

> **NIH NIH R00** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $248,760

## Abstract

PROJECT SUMMARY
Purinergic (P2X) receptors are trimeric, non-selective cation channels activated by ATP that play important
roles in cardiovascular, neuronal and immune systems. Despite their central function in human physiology and
as potential targets of therapeutic agents, the molecular mechanisms for P2X receptor antagonism are unclear,
especially for non-competitive antagonists where almost nothing is known. The study of P2X receptors has
been handicapped by a paucity of small molecules that serve as selective high-affinity agonists and
antagonists against the various receptor subtypes. Very recently, the applicant published atomic resolution
structures of human P2X3 (hP2X3) in an apo/resting state, an agonist-bound/open-pore state, an agonist-
bound/closed-pore/desensitized state and two competitive antagonist-bound states, identifying a novel
cytoplasmic domain that he hypothesizes plays a pivotal and unique structural role in receptor activation and
desensitization. The aims of this grant are designed to build off that work in order to firmly establish the
principles of P2X receptor antagonism, determine the structural role of key cytoplasmic residues involved in
P2X receptor activation and desensitization, and identify novel small molecule competitive and non-competitive
antagonists directed at homo-trimeric P2X1 and P2X3 receptor subtypes and hetero-trimeric P2X2,3 receptors,
utilizing ligand binding assays and electrophysiology to study function and X-ray crystallography and cryo
electron microscopy to study structure. This research will be carried out by an applicant with excellent training
in membrane protein biochemistry and a strong publication record. The training for this proposal will occur at
the Vollum Institute of Oregon Health and Science University under the mentorship of Dr. Eric Gouaux, a world
leader in the structural biology of ion channels and transporters who has previously transitioned numerous
post-doctoral trainees to independence. To prepare the applicant for a successful transition to independence,
Dr. Gouaux will oversee the candidate's structural biology training in cryo electron microscopy and continued
growth in X-ray crystallography. In addition to Dr. Gouaux, an institute of established investigators supports the
applicant with expertise in membrane protein biochemistry, ligand-receptor interactions/binding assays, and
the electrophysiology of ion channels. This training will be essential for the candidate to become an
independent investigator focused on studying the structure and function of purinergic receptors in order to
develop pharmacological agents for the treatment of cardiovascular conditions such as angina, hypertension,
and platelet aggregation.

## Key facts

- **NIH application ID:** 10438783
- **Project number:** 5R00HL138129-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Steven Elias Mansoor
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $248,760
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438783

## Citation

> US National Institutes of Health, RePORTER application 10438783, Structure/Function Studies on the Mechanisms of Purinergic Receptor Activation and Antagonism (5R00HL138129-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10438783. Licensed CC0.

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