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

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 molec...

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Detalles Bibliográficos
Autores principales: Sepuru, Krishna Mohan, Nair, Vinay, Prakash, Priyanka, Gorfe, Alemayehu A., Rajarathnam, Krishna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736917/
https://www.ncbi.nlm.nih.gov/pubmed/33344917
http://dx.doi.org/10.1016/j.isci.2020.101858
Descripción
Sumario: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.