title: Elucidating a key anti-HIV-1 and cancer-associated axis: the structure of CCL5 (Rantes) in complex with CCR5.
abstract: CCL5 (RANTES) is an inflammatory chemokine which binds to chemokine receptor CCR5 and induces signaling. The CCL5:CCR5 associated chemotactic signaling is of critical biological importance and is a potential HIV-1 therapeutic axis. Several studies provided growing evidence for the expression of CCL5 and CCR5 in non-hematological malignancies. Therefore, the delineation of the CCL5:CCR5 complex structure can pave the way for novel CCR5-targeted drugs. We employed a computational protocol which is primarily based on free energy calculations and molecular dynamics simulations, and report, what is to our knowledge, the first computationally derived CCL5:CCR5 complex structure which is in excellent agreement with experimental findings and clarifies the functional role of CCL5 and CCR5 residues which are associated with binding and signaling. A wealth of polar and non-polar interactions contributes to the tight CCL5:CCR5 binding. The structure of an HIV-1 gp120 V3 loop in complex with CCR5 has recently been derived through a similar computational protocol. A comparison between the CCL5 : CCR5 and the HIV-1 gp120 V3 loop : CCR5 complex structures depicts that both the chemokine and the virus primarily interact with the same CCR5 residues. The present work provides insights into the blocking mechanism of HIV-1 by CCL5.
authors: Department of Chemical and Biological Engineering, Princeton University, NJ, USA.
authors: Phanourios
authors: P
authors: Tamamis
authors: Department of Chemical and Biological Engineering, Princeton University, NJ, USA.
authors: Christodoulos A
authors: CA
authors: Floudas
mesh_terms: D000818:Animals; D001665:Binding Sites; D018946:Chemokine CCL5 / Q000737:chemistry* / Q000648:ultrastructure*; D003198:Computer Simulation; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000648:ultrastructure; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000737:chemistry / Q000648:ultrastructure; D011485:Protein Binding; D011487:Protein Conformation; D019713:Receptors, CCR5 / Q000737:chemistry* / Q000648:ultrastructure*
chemical_list: D018946:Chemokine CCL5; D015699:HIV Envelope Protein gp120; D009363:Neoplasm Proteins; D019713:Receptors, CCR5; C514793:gp120 protein, Human immunodeficiency virus 1