Chemokines CCL3 (Macrophage Inflammatory Protein 1α or MIP-1α) and CCL4 (MIP-1β) are crucial to immune responses to infection and inflammation. They can be induced in multiple activated cell types and can attract activated and memory T-cells to damaged sites [1,2]. CCL3 has a direct effect on T-cell differentiation . MIP-1 family members orchestrate acute and chronic inflammatory host responses at sites of injury or infection mainly by recruiting proinflammatory cells). They are crucial for T-cell chemotaxis from the circulation to inflamed tissue and also play an important role in the regulation of transendothelial migration of monocytes, dendritic cells, and NK cells . Despite their significant biological role, growing evidence has identified certain detrimental roles of the CCL3 : CCR5 and CCL4 : CCR5 complexes. The CCL3 : CCR5 signaling is associated with lung metastasis . In addition, CCL3/CCL4 secretion occurs due to B cell activation within lymphoid tissues, and this leads to the recruitment of CCR5+ regulatory T cell for cognate interactions with B cells and antigen representing cells [5,6]; this suggests that CCL3:CCR5 and CCL4:CCR5 axes possess a key role in chronic lymphocytic leukemia . Moreover, CCL3 and CCL4 are involved in multiple myeloma, melanoma, ovarian cancer [ref.  and references therein]. Due to the pivotal role of proteins CCL3 and CCL4 in cancer, and in additional human pathology, e.g., in diseases associated with the central nervous system, respiratory system gastro-intestinal system etc. [ref.  and references therein], the elucidation of the molecular recognition of CCR5 by CCL3 and CCL4 is of utmost importance.
We have introduced our computational protocol [10,11,12,13] which is primarily based on docking, binding free energy calculations, and molecular dynamics simulations, and present, what are to our knowledge, the first complete computationally derived structures of CCR5 in complex with CCL3 and CCL4 which are in remarkable agreement with previous experimental data. Our study identifies the functional role of the receptor and chemokine residues which are involved in binding and signaling. The computational protocol used in this study was enriched through the use of additional features such as targeted molecular dynamics simulations. We compare our findings with recent X-ray derived structures of a viral chemokine in complex with CXCR4  and chemokine CX3CL1 in complex with a viral G protein-coupled receptor . Our findings can be used to design novel CCR5-targeted potential therapeutic agents (e.g., for HIV and cancer).
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