# Structure, pharmacology and signaling of G protein-coupled receptors (GPCRs) in inflammation

> **NIH NIH R35** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $391,250

## Abstract

Project Summary
Inflammation is a complex process with many lipid and peptide mediators involved. A large number of these
mediators elicit either pro-inflammatory or pro-resolving effects through the action on G protein-coupled
receptors (GPCRs). Our research is focused on a group of GPCRs as close phylogenetic neighbors, which
comprises receptors for the pro-inflammatory mediators including anaphylatoxins, formylpeptides and
prostaglandin D2 (PGD2), and the newly discovered specialized pro-resolving lipid mediators (SPMs) including
lipoxin A4 (LXA4) and resolvins. The members of this GPCR family are active targets for developing new drugs
for a variety of inflammatory diseases. So far no structures have been reported for this family. Thus our
understanding of the molecular mechanisms underlying ligand action, receptor activation and signaling is quite
limited, which has impeded drug development. To fill this knowledge gap, recently we have obtained crystal
structures of two members in this family, the C5a receptor (C5aR) and the prostaglandin D2 receptor 2
(CRTH2). These two structures provided innovative information regarding the antagonism of C5aR and
CRTH2. We propose to further define the molecular determinants for the diverse pharmacological action of
C5aR and CRTH2 antagonists by testing novel hypotheses based our structures. We will take protein
crystallography and electron microscopy (EM) approaches in parallel to obtain high-resolution structures of
active C5aR and CRTH2 in complex with agonists and the Gi protein. The results will reveal the structural
basis of agonist binding and receptor activation. In addition, we propose to develop small-molecule antagonists
with new chemical scaffolds for C5aR and CRTH2 through structure-based drug design (SBDD) approach. We
will also test the possibility of developing extracellular conformational antibodies of C5aR and CRTH2 as new
pharmacological tools to block pro-inflammatory signaling pathways. The long-term goal is to move towards
the clinical investigation of such new agents for C5aR and CRTH2. Another long-term research direction is to
study GPCRs that mediate pro-resolving signaling pathways to promote inflammation resolution. FPR2/ALX
(formylpeptide receptor 2/LXA4 receptor) will be our primary research target. FPR2/ALX can be targeted by a
number of structurally unrelated mediators to mediate either pro-inflammatory or pro-resolving responses.
Research on this receptor is aimed to reveal the structural basis for the action of diverse ligands and the
molecular mechanism for the functional selectivity. Our study is significant for health because the discoveries
will facilitate the development of innovative pharmacological tools for both anti-inflammatory and pro-resolving
therapeutic strategies in the treatment of many inflammatory diseases.

## Key facts

- **NIH application ID:** 10453592
- **Project number:** 5R35GM128641-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** CHENG ZHANG
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $391,250
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10453592

## Citation

> US National Institutes of Health, RePORTER application 10453592, Structure, pharmacology and signaling of G protein-coupled receptors (GPCRs) in inflammation (5R35GM128641-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10453592. Licensed CC0.

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