title: Structural insight into a novel human CCR5-V130I variant associated with resistance to HIV-1 infection.
abstract: We report the identification of a novel CC chemokine receptor 5 (CCR5) variant that seems associated with resistance to HIV-1 infection. The V130I mutation of the CCR5 receptor is located in the intracellular loop ICL2 known as DRY box and described in the literature as a nonsynonymous mutation present in nonhuman primates group. Extensive molecular modeling and dynamics simulations were performed to elucidate the mechanism by which the V130I mutation may induce conformational change of the CCR5 folding protein and prevent the interaction with the β-arrestin protein. Our study provides new mechanistic insight into how a specific mutation in the regulatory domain of CCR5 might alter the structural folding of the DRY box and the possible ICL2 loop binding with the β-arrestin protein, as described in our previous computational study. The results from our large-scale simulations complement recent experimental results and clinical features and offer useful insights into the mechanism behind CCR5 protein folding and signal transduction. In order for HIV, the entry of the virus to the cells must fuse with the CCR5 receptor that sits on the surface of T-helper immune cells. The described V130I mutation in the gene encoding the CCR5 protein may results in a defective CCR5-Arrestin binding complex that blocks entry of the virus.
authors.affiliation: a Faculty of Sciences of Tunis, Laboratory of Genetics , Immunology and Human Pathology , Tunis , Tunisia .
authors.forename: Nejla
authors.initials: N
authors.lastname: Stambouli
authors.forename: Ning-Ning
authors.initials: NN
authors.lastname: Wei
authors.forename: Asma
authors.initials: A
authors.lastname: Jlizi
authors.forename: Samah
authors.initials: S
authors.lastname: Aissa
authors.forename: Rim
authors.initials: R
authors.lastname: Abdelmalek
authors.forename: Baderredine
authors.initials: B
authors.lastname: Kilani
authors.forename: Amine
authors.initials: A
authors.lastname: Slim
authors.forename: Ben Aissa Hanen
authors.initials: BA
authors.lastname: Tiouiri
authors.forename: Mahdi
authors.initials: M
authors.lastname: Dridi
authors.forename: Adel
authors.initials: A
authors.lastname: Hamza
authors.forename: Amel
authors.initials: A
authors.lastname: Ben Ammar Elgaied
mesh_terms: D000595:Amino Acid Sequence; D019390:Arrestins / Q000737:chemistry; D060467:Disease Resistance; D015658:HIV Infections / Q000235:genetics / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017510:Protein Folding; D019713:Receptors, CCR5 / Q000737:chemistry* / Q000235:genetics; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D019713:Receptors, CCR5; D000071557:beta-Arrestins
keywords: CCR5; HIV resistance; molecular dynamics; mutation; β-arrestin