@article{f269f4dbe4ba42a5a53268bb4a3698a8,
title = "Molecular basis of promiscuous chemokine binding and structural mimicry at the C-X-C chemokine receptor, CXCR2",
abstract = "Selectivity of natural agonists for their cognate receptors is a hallmark of G-protein-coupled receptors (GPCRs); however, this selectivity often breaks down at the chemokine receptors. Chemokines often display promiscuous binding to chemokine receptors, but the underlying molecular determinants remain mostly elusive. Here, we perform a comprehensive transducer-coupling analysis, testing all known C-X-C chemokines on every C-X-C type chemokine receptor to generate a global fingerprint of the selectivity and promiscuity encoded within this system. Taking lead from this, we determine cryoelectron microscopy (cryo-EM) structures of the most promiscuous receptor, C-X-C chemokine receptor 2 (CXCR2), in complex with several chemokines. These structural snapshots elucidate the details of ligand-receptor interactions, including structural motifs, which are validated using mutagenesis and functional experiments. We also observe that most chemokines position themselves on CXCR2 as a dimer while CXCL6 exhibits a monomeric binding pose. Taken together, our findings provide the molecular basis of chemokine promiscuity at CXCR2 with potential implications for developing therapeutic molecules.",
keywords = "biased signaling, chemokine receptors, cryo-EM, dimerization, drug discovery, GPCRs, ligand promiscuity, signal transduction, structural mimicry, β-arrestin",
author = "Shirsha Saha and Sano, {Fumiya K.} and Saloni Sharma and Manisankar Ganguly and Sudha Mishra and Annu Dalal and Hiroaki Akasaka and Kobayashi, {Takaaki A.} and Nashrah Zaidi and Divyanshu Tiwari and Nabarun Roy and Yadav, {Manish K.} and Nilanjana Banerjee and Sayantan Saha and Samanwita Mohapatra and Yuzuru Itoh and Andy Chevign{\'e} and Ramanuj Banerjee and Wataru Shihoya and Osamu Nureki and Shukla, {Arun K.}",
note = "Funding: Research in A.K.S.{\textquoteright}s laboratory is supported by the Senior Fellowship of the DBT Wellcome Trust India Alliance (IA/S/20/1/504916) awarded to A.K.S., the Science and Engineering Research Board (SPR/2020/000408 and IPA/2020/000405), the Indian Council of Medical research (F.NO.52/ 15/2020/BIO/BMS), and IIT Kanpur. A.K.S. is the Sonu Agrawal Memorial Chair Professor. Shirsha Saha is funded by the Prime Minister{\textquoteright}s Research Fellowship (PMRF). This work was supported by grants from the JSPS KAKENHI, grant numbers 21H05037 (O.N.), 22K19371 and 22H02751 (W.S.), and 23KJ0491 (F.K.S.); the Kao Foundation for Arts and Sciences (W.S.); the Takeda Science Foundation (W.S.); the Lotte Foundation (W.S.); and the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research [BINDS]) from the Japan Agency for Medical Research and Development (AMED), grant numbers JP22ama121012 (O.N.) and JP22ama121002 (support number 3272; O.N.). A.C. was sup- ported by the Luxembourg Institute of Health (LIH) through the NanoLux Platform, the Luxembourg National Research Fund (INTER/ FNRS grants INTER 20/15084569 and CORE C23/BM/18068832), and the F.R.S.-FNRS-Te{\' } le{\' } vie (grant numbers 7.8504.20, 7.4502.21, and 7.8508.22) Publisher Copyright: {\textcopyright} 2025 Elsevier Inc.",
year = "2025",
month = mar,
day = "6",
doi = "10.1016/j.molcel.2025.01.024",
language = "English",
volume = "85",
pages = "976--988.e9",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "5",
}