Molecular Mechanism of Action for Allosteric Modulators and Agonists in CC-chemokine Receptor 5 (CCR5).

ABSTRACT: The small molecule metal ion chelators bipyridine and terpyridine complexed with Zn²⁺ (ZnBip and ZnTerp) act as CCR5 agonists and strong positive allosteric modulators of CCL3 binding to CCR5, weak modulators of CCL4 binding, and competitors for CCL5 binding. Here we describe their binding site using computational modeling, binding, and functional studies on WT and mutated CCR5. The metal ion Zn²⁺ is anchored to the chemokine receptor-conserved Glu-283^VII:06/7.39 Both chelators interact with aromatic residues in the transmembrane receptor domain. The additional pyridine ring of ZnTerp binds deeply in the major binding pocket and, in contrast to ZnBip, interacts directly with the Trp-248^VI:13/6.48 microswitch, contributing to its 8-fold higher pot

SUBMITTER: Karlshoj S 

PROVIDER: S-EPMC5207192 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature