Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV

Abstract

Summary CCR5 is the primary chemokine receptor utilized by HIV to infect leukocytes, whereas CCR5 ligands inhibit infection by blocking CCR5 engagement with HIV gp120. To guide the design of improved therapeutics, we solved the structure of CCR5 in complex with chemokine antagonist [5P7]CCL5. Several structural features appeared to contribute to the anti-HIV potency of [5P7]CCL5, including the distinct chemokine orientation relative to the receptor, the near-complete occupancy of the receptor binding pocket, the dense network of intermolecular hydrogen bonds, and the similarity of binding determinants with the FDA-approved HIV inhibitor Maraviroc. Molecular modeling indicated that HIV gp120 mimicked the chemokine interaction with CCR5, providing an explanation for the ability of CCR5 to recognize diverse ligands and gp120 variants. Our findings reveal that structural plasticity facilitates receptor-chemokine specificity and enables exploitation by HIV, and provide insight into the design of small molecule and protein inhibitors for HIV and other CCR5-mediated diseases.

The solution structure of monomeric CCL5 in complex with a doubly sulfated N‐terminal segment of CCR5

“…As supported by previous experimental data and the recent crystal structure of CCR5 bound to a high‐affinity CCL5 variant , CCR5 is thought to interact with monomeric CCL5. At micromolar concentrations in solution, wild‐type CCL5 self associates to form high‐molecular weight aggregates , a characteristic which is problematic for high‐resolution NMR structural characterization of the receptor:chemokine interaction.…”

Remodeling our concept of chemokine receptor function: From monomers to oligomers

“…Mutation of these residues in CCR5 blocks dimerization and the response to CCL5 stimulus . The crystal structure of CCR5 in the presence of the HIV‐1 inhibitor maraviroc, only support the existence of monomers . A cyclic helix‐forming peptide mimetic, based on the human CCR2 dimerization region, specifically blocked CCL2‐mediated monocyte migration, suggesting an important role of TM‐I in CCR2 dimerization .…”

Development of Mimokines, chemokine N terminus-based CXCR4 inhibitors optimized by phage display and rational design

“…A prerequisite to the design and development of potent‐specific receptor antagonists is the knowledge of the interaction mode of the receptor with its ligand. The substantial amount of mutational and functional data accumulated over the years allowed to gain precise insight into the chemokine‐binding mode, moving from a simple two‐step mechanism in which the contacts between the receptor N‐terminal part and the core of the chemokine (CRS1) enable the correct orientation of the chemokine N terminus to penetrate into the receptor transmembrane domain (CRS2); to a more continuous one, characterized by extensive contacts between the two partners . According to both models, the main pharmacophore determinant modulating the chemokine biological activity and selectivity is present in its N‐terminal part.…”