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

> **NIH NIH R35** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $434,659

## 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). My lab is interested in the molecular mechanisms by which pro-inflammatory and pro-
resolving GPCRs sense diverse signaling molecules and transduce chemical signals across the cell membrane
to regulate inflammation. We employ a combination of research approaches in structural biology including cryo-
electron microscopy (cryo-EM), pharmacology, and computational biology. We are also making efforts to develop
novel ligands of those GPCRs as potential new drugs through structure-based approaches. In the last funding
period, we have determined structures of several members of a chemotactic GPCR family including the C5a
receptor (C5aR), the prostaglandin D2 receptor 2 (DP2), and the formylpeptide receptors bound to diverse
agonists or antagonists at different conformational states, which allowed us to define the molecular basis for the
action of several drugs and drug candidates. In the current proposal, we will study the signaling and
pharmacology of three lipid GPCRs that regulate different aspects of inflammation, the chemerin receptor
CMKLR1 (ChemR23), GPR32, and GPR84. Both CMKLR1 and GPR32 are closely related to the C5aR, DP2
and FPRs. They have been shown to respond to resolvins, which are SPMs derived from ω-3 polyunsaturated
fatty acids (PUFAs), to induce the resolution of inflammation. In contrast, GPR84 is a newly characterized pro-
inflammatory GPCR that can be activated by endogenous medium-chain fatty acids (MCFAs) to augment
inflammatory responses and enhance phagocytosis by macrophages. For the next five years, we aim to provide
a comprehensive molecular understanding of how diverse lipid, peptide, and synthetic small-molecule ligands
act on and regulate the activities of these three lipid GPCRs. Our studies will exploit unique properties of
CMKLR1, GPR32, and GPR84 to address several fundamental issues of GPCR signaling and pharmacology
including lipid recognition, receptor antagonism, allosteric modulation, and biased signaling. Our research
strategies developed in this proposal will be applied to our future research on the structure and pharmacology of
other fatty acid receptors (FFARs) in immunometabolism. We will also identify new hit compounds for these
GPCRs in the next five years, which will be further developed in future as useful pharmacological tools and
potential drugs to control inflammation.

## Key facts

- **NIH application ID:** 10764432
- **Project number:** 2R35GM128641-06
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** CHENG ZHANG
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $434,659
- **Award type:** 2
- **Project period:** 2018-08-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764432

## Citation

> US National Institutes of Health, RePORTER application 10764432, Structure, pharmacology and signaling of G protein-coupled receptors (GPCRs) in inflammation (2R35GM128641-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10764432. Licensed CC0.

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