# Structural Basis of chemokine CXCL1 recognition with CXCR2 receptor

> **NIH NIH R21** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2022 · $200,000

## Abstract

Chemokine CXCL1, and its receptor CXCR2, a class-A G protein-coupled receptor (GPCR), play a
crucial role in directing blood neutrophils to sites of infection and injury. A dysregulation in CXCR2
activation results in host tissue damage and disease. CXCL1 binds CXCR2 at two distinct sites: N-
terminal domain (Site-I, unique to chemokines) and a groove defined by the receptor extracellular
loops/transmembrane helices (Site-II, shared with all class A receptors). The molecular basis by
which chemokine binding two distinct sites determine CXCR2 activation is not known. Structures and
sequence analyses reveal that chemokine and receptor residues that mediate binding are either
unstructured or conformationally dynamic. We propose that CXCL1 binding at Site-I of CXCR2, the
initial obligatory step, triggers structural and dynamic changes that are essential for Site-II
interactions. We will test our hypothesis using a hybrid strategy that combines nuclear magnetic
resonance (NMR) spectroscopy and molecular dynamics (MD) simulations. We will determine the
structure and characterize the role of conformational dynamics of Site-I CXCL1-CXCR2 N-terminal
domain complex using NMR spectroscopy (Aim 1). We will generate a structural model of CXCL1
bound to CXCR2 at the N-terminal domain by merging Site-I NMR structure and previously
determined CXCR2 structure, and use extended MD simulations to describe how CXCL1 bound at
Site-I engages the receptor at Site-II (Aim 2). We will characterize how CXCL1 Site-I and Site-II
residues identified from Aims 1 and 2 mediate CXCR2 activation using cellular assays (Aim 3). These
studies will provide critical insights into the molecular mechanisms underlying CXCR2 activation and
will advance designing therapeutics that disrupt CXCR2 activation and alleviate disease.

## Key facts

- **NIH application ID:** 10488181
- **Project number:** 5R21AI160613-02
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Krishna Rajarathnam
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $200,000
- **Award type:** 5
- **Project period:** 2021-09-13 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488181

## Citation

> US National Institutes of Health, RePORTER application 10488181, Structural Basis of chemokine CXCL1 recognition with CXCR2 receptor (5R21AI160613-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10488181. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*