Long-Range Coupled Motions Underlie Ligand Recognition by a Chemokine Receptor

Krishna Mohan Sepuru; Vinay Nair; Priyanka Prakash; Alemayehu A Gorfe; Krishna Rajarathnam

doi:10.1016/j.isci.2020.101858

Long-Range Coupled Motions Underlie Ligand Recognition by a Chemokine Receptor

iScience. 2020 Nov 26;23(12):101858. doi: 10.1016/j.isci.2020.101858. eCollection 2020 Dec 18.

Authors

Krishna Mohan Sepuru^{1

2}, Vinay Nair^{3

4}, Priyanka Prakash³, Alemayehu A Gorfe^{3

4}, Krishna Rajarathnam^{1

5

2}

Affiliations

¹ Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77555, USA.
² Sealy Center for Structural Biology and Molecular Biophysics, The University of Texas Medical Branch, Galveston, TX 77555, USA.
³ Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁴ MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
⁵ Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555, USA.

Abstract

Chemokines are unusual class-A G protein-coupled receptor agonists because of their large size (∼10 kDa) and binding at two distinct receptor sites: N-terminal domain (Site-I, unique to chemokines) and a groove defined by extracellular loop/transmembrane helices (Site-II, shared with all small molecule class-A ligands). Structures and sequence analysis reveal that the receptor N-terminal domains (N-domains) are flexible and contain intrinsic disorder. Using a hybrid NMR-MD approach, we characterized the role of Site-I interactions for the CXCL8-CXCR1 pair. NMR data indicate that the CXCR1 N-domain becomes structured on binding and that the binding interface is extensive with 30% CXCL8 residues participating in this initial interaction. MD simulations indicate that CXCL8 bound at Site-I undergoes extensive reorganization on engaging Site-II with several residues initially engaged at Site-I also engaging at Site-II. We conclude that structural plasticity of Site-I interactions plays an active role in driving ligand recognition by a chemokine receptor.

Keywords: Biochemistry; Computational Molecular Modelling; Molecular Dynamics; Structural Biology.

Grants and funding

R01 GM124233/GM/NIGMS NIH HHS/United States