Structural insight into the binding complex: β-arrestin/CCR5 complex

• Published in: Journal of biomolecular structure & dynamics Vol. 32; no. 6; pp. 866 - 875
• Main Authors: Stambouli, Nejla, Dridi, Mehdi, Wei, Ning-Ning, Jlizi, Asma, Bouraoui, Abderahmen, Elgaaied, Amel Ben Ammar
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 03.06.2014
• Subjects: Amino Acid Sequence; Arrestins - chemistry; beta-Arrestins; Binding Sites; CCR5; docking; HIV; Humans; Molecular Docking Simulation; molecular dynamics; Molecular Dynamics Simulation; Molecular Sequence Data; normal mode analysis; Protein Interaction Domains and Motifs; Protein Structure, Tertiary; Receptors, CCR5 - chemistry; Sequence Homology, Amino Acid; Thermodynamics; β-arrestin
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2013.794373

The chemokine receptor 5 (CCR5) belongs to the superfamily of serpentine G protein-coupled receptors (GPCRs). The DRY motif (Asp, Arg, Tyr) of the intracellular loop 2 (ICL2), which is highly conserved in the GPCRs has been shown to be essential for the stability of folding of CCR5 and the interaction with β-arrestin. But the molecular mechanism by which it recognizes and interacts with β-arrestin has not been elucidated. In the present study, we described the active state of the β-arrestin structure using normal mode analysis and characterized the binding cleft of CCR5-ICL2 with β-arrestin using SABRE© docking tool and molecular dynamics simulation. Based on our computational results, we proposed a mode of binding between the ICL2 loop of CCR5 and β-arrestin structure, and modeled the energetically stable β-arrestin/CCR5 complex. In view of CCR5's importance as a therapeutic target for the treatment of HIV, this observation provides novel insight into the β-arrestin/CCR5 pathway. As a result, the current computational study of the detailed β-arrestin/CCR5 binding complex could provide the rationale for the development of next generation of HIV peptide inhibitors as therapeutic agents.