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Proteins. 2012 Aug;80(8):1919-28. doi: 10.1002/prot.24099. Epub 2012 May 25.

Characterization of the homodimerization interface and functional hotspots of the CXCR4 chemokine receptor.

Author information

1
Fundación Pública Galega de Medicina Xenómica, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.

Abstract

The recent crystallographic structures of the human chemokine CXC Receptor 4 (CXCR4) provide experimental evidence of a human G Protein-Coupled Receptor (GPCR) dimer in atomic detail. The CXCR4 homodimers reveal an unexpected dimerization mode involving transmembrane helices TM5 and TM6, which is examined here using all-atom molecular dynamics (MD) simulations in the physiological environment of a lipid bilayer. The bacteriophage T4 lysozyme (T4L), which was fused to the crystallized protein but absent in our simulations, is found to slightly affect the observed relative position of the protomers in the two dimers studied here, and consequently some rearrangements of the dimerization interface are proposed. In addition, the simulations provide further evidence about the role of the two stabilizing single point mutations introduced to crystallize the receptor. Finally, this work analyzes the structural and dynamic role of key residues involved both in ligand binding and in the infection process of HIV. In particular, the different side chain conformations of His113(3.39) are found to influence the dynamics of the surrounding functional hotspot region being evaluated both in the presence and in the absence of the co-crystallized ligand IT1t. The analysis reported here adds valuable knowledge for future structure-based drug design (SBDD) efforts on this pharmacological target.

PMID:
22513895
DOI:
10.1002/prot.24099
[Indexed for MEDLINE]

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