Journal of Molecular Modeling

, Volume 9, Issue 5, pp 329–336

Structural and functional characterization of the human CCR5 receptor in complex with HIV gp120 envelope glycoprotein and CD4 receptor by molecular modeling studies

Original Paper

DOI: 10.1007/s00894-003-0154-9

Cite this article as:
Liu, S., Fan, S. & Sun, Z. J Mol Model (2003) 9: 329. doi:10.1007/s00894-003-0154-9


The entry of human immunodeficiency virus (HIV) into cells depends on a sequential interaction of the gp120 envelope glycoprotein with the cellular receptors CD4 and members of the chemokine receptor family. The CC chemokine receptor CCR5 is such a receptor for several chemokines and a major coreceptor for the entry of R5 HIV type-1 (HIV-1) into cells. Although many studies focus on the interaction of CCR5 with HIV-1, the corresponding interaction sites in CCR5 and gp120 have not been matched. Here we used an approach combining protein structure modeling, docking and molecular dynamics simulation to build a series of structural models of the CCR5 in complexes with gp120 and CD4. Interactions such as hydrogen bonds, salt bridges and van der Waals contacts between CCR5 and gp120 were investigated. Three snapshots of CCR5–gp120–CD4 models revealed that the initial interactions of CCR5 with gp120 are involved in the negatively charged N-terminus (Nt) region of CCR5 and positively charged bridging sheet region of gp120. Further interactions occurred between extracellular loop2 (ECL2) of CCR5 and the base of V3 loop regions of gp120. These interactions may induce the conformational changes in gp120 and lead to the final entry of HIV into the cell. These results not only strongly support the two-step gp120–CCR5 binding mechanism, but also rationalize extensive biological data about the role of CCR5 in HIV-1 gp120 binding and entry, and may guide efforts to design novel inhibitors.

Figure Three structural models of CCR5 in complex with gp120–CD4. These represent snapshots of different intermediates of the complex that characterize the dynamic interaction process of CCR5 with gp120. The ribbon diagram shows gp120 in red, the two N-terminal domains of CD4 in yellow, and CCR5 in blue. The Nt, ECL1, 2, and 3 in CCR5, as well as the bridging sheet and V3 loop base of gp120 are labeled. Model I shows that Nt begins to interact with the bridging sheet, the ECLs of CCR5 do not interact with gp120 and there is a big gap between them. It is a snapshot of the initial recognition of CCR5 with gp120. Model III shows that ECL2 begins to interact with the V3 loop base in addition to the interaction between Nt and the bridging sheet. It is a snapshot of the transition state of the binding process. Model II shows the full interaction between CCR5 and gp120. More residues within Nt interact with the bridging sheet, ECL2 and ECL3 interact with the V3 base loop and bridging sheet, respectively. It is a snapshot of a "fusion-active" state prior to virus entry. The interaction intensities between CCR5 and gp120 are model I<model III<model II


CCR5 Gp120 Interaction Docking Molecular dynamics simulation Complex 

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  1. 1.Institue of Bioinformatics, Department of Biological Sciences and BiotechnologyTsinghua UniversityBeijingPeople's Republic of China
  2. 2.Cellular and Molecular Evolutionary Key Laboratory, Kunming Institute of ZoologyChinese Academy of SciencesKunmingPeople's Republic of China

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