Structure analysis of CCR5 from human and primates

It is well known that the chemokine receptor CCR5 plays very important role s in HIV-1 virus infection. A three-dimensional molecular model of human CC R5 was generated by SYBYL, a distance geometry-based homologous modeling pa ckage, using the corresponding transmembrane domain of bacteriorhodopsin as the template. On the basis of human CCR5 model, we also built 18 3D molecu lar models of CCR5 in primates from Pongo pygmaeus, Pygathrix nemaeus, Maca ca assameniss, Trachy-pithecus phayrei, T. francoisi, M. arotoides, Rhinopi thecus roxellance, R, bieti, R. avunculus, Hylobates leucogenys, Pan troglo dytes, Gorilla gorilla, Cercopithecus aethiops 1, C. aethiops 2, Papio hama dryas M. mulatta, M. fascicularis and M. nemestrina. Structural analyses an d statistics results suggested that the main-chains of the primate CCR5 wer e similar to that of the human CCR5 and that the fit-RMS deviation values o f these primate CCR5 were less than 0.1 Angstrom. Moreover, the structures of these CCR5 proteins, except those of the African green monkey 1 (C.aet1) , do not have a remarkable difference. It is proved that the 14th residue i s possibly very important in the inhibition infections by M-tropic HIV-1, a nd it is also demonstrated that the 13th residue of human CCR5 was changed from asparagine into aspartic acid in all these primates. It means that the primate CCR5 no longer depend on CD4 for efficient entry, but human CCR5 m ay have evolved subsequently due to the use of CD4 as a receptor, allowing the high-affinity chemokine receptor-binding site of HIV to be sequestered from host immune surveillance. (C) 2000 Elsevier Science B.V. All rights re served.