In silico analysis reveals sequential interactions and protein conformational changes during the binding of chemokine CXCL-8 to its receptor CXCR1.
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.
Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, Taiwan; Nanotechnology Research Center, National Dong Hwa University, Hualien, Taiwan.
Je-Wen
JW
Liou
Department of Life Sciences, Tzu Chi University, Hualien, Taiwan.
Fang-Tzu
FT
Chang
Department of Life Sciences, Tzu Chi University, Hualien, Taiwan.
Yi
Y
Chung
Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, Taiwan.
Wen-Yi
WY
Chen
Institute of Biophotonics, School of Biomedical Science and Engineering and Biophotonics & Molecular Imaging Research Center (BMIRC), National Yang Ming University, Taipei, Taiwan.
Wolfgang B
WB
Fischer
Department of Life Sciences, Tzu Chi University, Hualien, Taiwan.
Hao-Jen
HJ
Hsu
D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D016209:Interleukin-8 / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D023062:Receptors, Interleukin-8A / Q000737:chemistry* / Q000378:metabolism*
D016209:Interleukin-8; D008024:Ligands; D008051:Lipid Bilayers; D023062:Receptors, Interleukin-8A