Structure of the CCR5 chemokine receptor – HIV entry inhibitor Maraviroc complex
By Q. Tan, Ya Zhu, Jian Li, Zhuxi Chen, G. Han, Irina Kufareva, Tingting Li, Limin Ma, G. Fenalti, Jing Li and 9 more. Science, 2013
705 citations recorded by the source corpus.
CCR5-Maraviroc Structure The chemokine receptor CCR5, a G protein–coupled receptor best known as a co-receptor during HIV-1 infection, is important in a variety of physiological processes. Tan et al. (p. 1387, published online 12 September; see the Perspective by Klasse) now report the high-resolution crystal structure of CCR5 bound to the HIV-1 entry inhibitor, Maraviroc. The structure suggests that Maraviroc acts as a noncompetitive inhibitor by binding to a region of CCR5 that is distinct from the binding site of HIV-1 and chemokines. Comparison of the structure of CCR5 with the other HIV-1 co-receptor, the chemokine receptor CXCR4, provides insight into the co-receptor selectivity of the virus. The crystal structure of the HIV co-receptor CCR5 bound to the HIV drug maraviroc provides insight into how HIV enters cells. [Also see Perspective by Klasse] The CCR5 chemokine receptor acts as a co-receptor for HIV-1 viral entry. Here we report the 2.7 angstrom–resolution crystal structure of human CCR5 bound to the marketed HIV drug maraviroc. The structure reveals a ligand-binding site that is distinct from the proposed major recognition sites for chemokines and the viral glycoprotein gp120, providing insights into the mechanism of allosteric inhibition of chemokine signaling and viral entry. A comparison between CCR5 and CXCR4 crystal structures, along with models of co-receptor–gp120-V3 complexes, suggests that different charge distributions and steric hindrances caused by residue substitutions may be major determinants of HIV-1 co-receptor selectivity. These high-resolution insights into CCR5 can enable structure-based drug discovery for the treatment of HIV-1 infection.
Subfields: Immunology, Oncology, Virology
View Paper: https://www.semanticscholar.org/paper/41745affea94de86618f738b5019535dd4fcde0e
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Citations in the corpus
- Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV (2017, background): “From this screen, a complex between CCR5 with an intracellular loop 3 (ICL3) rubredoxin fusion ((Tan et al., 2013), referred to as CCR5) and the antagonist variant [5P7]CCL5 (containing a 10-residue N-terminal sequence 0-QGPPLMALQS-9 in place of the 9-residue sequence 1-SPYSSDTTP-9 in WT CCL5)…”
- A Structural Framework for GPCR Chemogenomics: What's In a Residue Number? (2018, methodology): “4, PDB: 4MBS [110]) using the BW and generic numbering.”
- International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors (2014, neutral): “maraviroc complex has recently been solved (Tan et al., 2013).”