# Molecular basis of complement anaphylatoxin receptor activation, regulation, selectivity and signaling bias

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $580,563

## Abstract

Abstract – Molecular basis of complement anaphylatoxin receptor activation, regulation, selectivity and
signaling bias
The complement system is a vital part of the immune system, involved in promoting inflammation and clearance
of pathogens. Dysregulation of this system has been linked to various diseases, including autoimmune disorders,
neurodegenerative conditions, and cancer. Understanding the molecular mechanisms underlying complement
activation and signaling is crucial for therapeutic development. This study aims to investigate the molecular basis
of complement anaphylatoxin receptor activation, regulation, selectivity, and signaling bias. As part of our
studies, we will obtain valuable insights through structural determination and characterization of these receptors,
revealing unique binding pocket topologies and details of receptor activation, and signaling. The specific aims of
the study are: 1) elucidating the mechanisms of receptor activation and beta-arrestin recruitment, 2) identifying
molecular determinants of signaling bias and receptor selectivity, and 3) investigating immune response
regulation and antagonism of complement receptors. The research strategy involves cryo-electron microscopy,
signaling assays, and structural and biochemical techniques. The significance of this work lies in its potential to
advance our understanding of complement receptor biology, provide frameworks for drug design, and offer new
insights into immunomodulatory roles of these receptors. The findings could lead to the development of novel
compounds and contribute to the understanding of complement receptor functions in physiology and disease
contexts. This study represents one of the most comprehensive investigations of any GPCR subfamily to date
and aims to address long-standing questions regarding ligand selectivity, signaling bias, regulation, and
antagonism. The results will have implications for the development of tool compounds and therapeutic
interventions targeting complement receptors and have the potential to impact a wide range of diseases
associated with complement system dysfunction.

## Key facts

- **NIH application ID:** 10860476
- **Project number:** 1R01AI182224-01
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Cornelius Gati
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $580,563
- **Award type:** 1
- **Project period:** 2024-04-15 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10860476

## Citation

> US National Institutes of Health, RePORTER application 10860476, Molecular basis of complement anaphylatoxin receptor activation, regulation, selectivity and signaling bias (1R01AI182224-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10860476. Licensed CC0.

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