Structural analysis of human CCR2b and primate CCR2b by molecular modeling and molecular dynamics simulation

Abstract

CCR2b, a chemokine receptor for MCP-1, -2, -3, -4, plays an important role in a variety of diseases involving infection, inflammation, and/or injury, as well as being a coreceptor for HIV-1 infection. Two models of human CCR2b (hCCR2b) were generated by homology modeling and 1 ns restrained molecular dynamics (MD) simulation. In one only C113-C190 forms a disulfide bond (SS model); in another the potential C32-C277 disulfide bond was formed (2SS model). Analysis of the structures and averaged displacements of Calpha atoms of the N-terminal residues shows that the main differences between the SS and 2SS models lie in a region D25YDYGAPCHKFD36; in the extracellular part of the 2SS model the accessible surfaces of N12, F23, Y26, Y28 and F35 are obviously raised and a more stable H-bond net is formed. The potential energy of the 2SS-water assembly finally fluctuated around -43,020 kJ x mol(-1), which is about 302 kJ x mol(-1) lower than that of the SS-water assembly. All these results suggest that the 2SS model is more favorable. The CCR2b genes of 17 primates were sequenced and four CCR2b models for primates Ateles paniscus (A. pan), Hylobates leucogyneus(H. leu), Papio cynocephalus (P. cyn) and Trachypithecus francoist ( T. fra) were generated based on the 2SS model. A comparison of hCCR2b with primate CCR2b also supports the importance of the region D25YDYGAPCHKFD36. Electrostatic potential maps of human and primate CCR2b all display the dipolar characteristics of CCR2b with the negative pole located in the extracellular part and a strong positive pole in the cytoplasmic part. Based on the CCR2b model, we suggest that the main functional residues fall in the D25YDYGAPCHKFD36 region, and the negative electrostatic feature is a non-specific, but necessary, factor for ligands or gp120/CD4 binding.

Investigation of the Binding Site of CCR2 using 4-Azetidinyl-1-aryl-cyclohexane Derivatives: A Membrane Modeling and Molecular Dynamics Study

“…Previously homology models of CCR2 were developed using the traditionally used bovine rhodopsin and the recently reported β 2 -adrenergic receptors as templates. 21,[54][55][56] In this study we used the recently reported CXCR4 (PDB code: 3ODU) as a template and modeling was done because of the non-availability of crystal structure. A molecular docking study was then performed with 16b of 4AAC against the proposed binding site.…”

In-silico Modeling of Chemokine Receptor CCR2 And CCR5 to Assist the Design of Effective and Selective Antagonists

“…al. reported a modeled structure for CCR2 (PDB code: 1KP1) and it is publicly available [22] . The alignment used for the model development and the model obtained after MD analysis is shown in Fig.…”

Homology modeling of human CCR2 receptor

“…Furthermore, the residues shown in color under the query sequence but not in the template sequence are identical to the residues present in bovine rhodopsin. Bovine rhodopsin was used as a template for some previously reported homology models of CCR2 (Berkhout et al, 2003;Mirzadegan et al, 2000;Shi et al, 2002 identity between bovine rhodopsin and CCR2 is 21% while between human b 2 -adrenoceptor and CCR2 receptor is 24%.…”

“…Shi et al also developed two homology models of CCR2b receptor taking bovine rhodopsin as the template. In one of the models, there was only one disulfide bond (1KAD) while in the other (1KP1) there are two disulfide bonds (Shi et al, 2002). Hence, one can develop a homology model of human CCR2 receptor with the help of newly available crystal structures of GPCRs such as human b 2 -adrenoceptor (2007), human A2A adenosine receptor (2008), and turkey b 1 -adrenoceptor (2008).…”