In Silico Analysis Reveals Sequential Interactions and Protein Conformational Changes during the Binding of Chemokine CXCL-8 to Its Receptor CXCR1

Je-Wen Liou,Wolfgang B Fischer,Yi Chung,Wen-Yi Chen,Hao-Jen Hsu,Fang-Tzu Chang,Maik Behrens

doi:10.1371/journal.pone.0094178

Je-Wen Liou, Wolfgang B Fischer + Show 5 more

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https://doi.org/10.1371/journal.pone.0094178

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Abstract

Chemokine CXCL-8 plays a central role in human immune response by binding to and activate its cognate receptor CXCR1, a member of the G-protein coupled receptor (GPCR) family. The full-length structure of CXCR1 is modeled by combining the structures of previous NMR experiments with those from homology modeling. Molecular docking is performed to search favorable binding sites of monomeric and dimeric CXCL-8 with CXCR1 and a mutated form of it. The receptor-ligand complex is embedded into a lipid bilayer and used in multi ns molecular dynamics (MD) simulations. A multi-steps binding mode is proposed: (i) the N-loop of CXCL-8 initially binds to the N-terminal domain of receptor CXCR1 driven predominantly by electrostatic interactions; (ii) hydrophobic interactions allow the N-terminal Glu-Leu-Arg (ELR) motif of CXCL-8 to move closer to the extracellular loops of CXCR1; (iii) electrostatic interactions finally dominate the interaction between the N-terminal ELR motif of CXCL-8 and the EC-loops of CXCR1. Mutation of CXCR1 abrogates this mode of binding. The detailed binding process may help to facilitate the discovery of agonists and antagonists for rational drug design.

Highlights

Chemokines regulate a wide range of biological and pathological processes by recruiting leukocytes to the site of injury and infection to embryogenesis, wound healing, metastasis, innate immunity and angiogenesis [1,2,3]
Since the binding of the CXCL-8 to CXCR1 are central in various biological processes and signal transduction pathways, it will be of great importance to understand the exact interactions between CXCL-8 and CXCR1 in the structural point of view
The root-mean-square fluctuation (RMSF) values per-residue of the CXCR1 indicate that the Nterminus (N-ter), extracellular loops (EC2-3, EC4-5, and EC6-7), intracellular loops (IC1-2, IC3-4, and IC5-6), and C-terminus (Cter) generally have a higher fluctuation value compare to the transmembrane (TM) regions (Figure S1)

Summary

Introduction

Chemokines regulate a wide range of biological and pathological processes by recruiting leukocytes to the site of injury and infection to embryogenesis, wound healing, metastasis, innate immunity and angiogenesis [1,2,3]. Chemokines carry out their function by binding to and activation of the G-protein-coupled receptors (GPCRs) on the cell surface. Upon binding of CXCL-8 to the receptor on the neutrophils, CXCR1 undergoes conformational changes resulting in signal transduction by activating the Gai subunit, leading to the release of Gbc subunits [5]. Since the binding of the CXCL-8 to CXCR1 are central in various biological processes and signal transduction pathways, it will be of great importance to understand the exact interactions between CXCL-8 and CXCR1 in the structural point of view

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