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Molecular Dynamics Simulation of Chemokine Receptors in Lipid Bilayer: A Case Study on C-C Chemokine Receptor Type 2 Publisher Pubmed



Shahlaei M1 ; Fassihi A2 ; Papaleo E3 ; Pourfarzam M4
Authors

Source: Chemical Biology and Drug Design Published:2013


Abstract

Chemokine receptors belong to the membrane proteins that are included in many physiological phenomena. However, the mechanism of their action is unknown at the atomistic level in different aspects. In this study, a computational pipeline is exploited to investigate the molecular basis of how the structure of C-C chemokine receptor type 2, a prototypical chemokine receptor, is affected by lipid bilayer and an antagonist (INCB3344). This study includes homology modeling, molecular dynamics simulation in lipid bilayer, and docking. A detailed mechanism of INCB3344 has been described. Tyr 49, Trp 98, Tyr 120, His 121, and Glu 291 are proved to play important roles in binding. Integrating results obtained in this study and experimental data help us to suggest a two-step ligand-binding mechanism. The N-terminus of protein first sticks out from the extracellular domain suitable for the contact with the antagonist. Binding of ligand to this segment leads to the geometrical changes to facilitate the ligand interactions with extracellular loop 2 of C-C chemokine receptor type 2. Finally, the interactions occurring between extracellular loop 2 and ligand induce conformational changes in C-C chemokine receptor type 2 structure. These changes bring the ligand closer to the binding pocket, allowing the interaction between INCB3344 and the residues of active site. In this study, a computational pipeline is exploited to investigate the molecular basis of how the structure of C-C chemokine receptor type 2 is affected by lipid bilayer and antagonist (INCB3344) explicitly. © 2013 John Wiley & Sons A/S.
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