BioCentury
ARTICLE | Distillery Techniques

Drug platforms

January 11, 2017 12:49 AM UTC

Crystallographic studies of CCR9 and CCR2 bound to antagonists could aid the design of allosteric inhibitors of chemokine receptors. Structural analysis of a 315-residue region of a mutant, thermostabilized version of CCR9 complexed with the allosteric CCR9 antagonist Traficet-EN vercirnon and a 329-residue region of CCR2 fused to T4 lysozyme and complexed with orthosteric and allosteric antagonist tool compounds revealed the allosteric antagonists bound to an intracellular allosteric pocket enclosed by helices I to III and VI to VIII in their respective receptors. Mutagenesis studies of the CCR9 allosteric site identified five residues involved in the binding interaction and sequencing showed the binding site was conserved across multiple chemokine receptors. In in vitro CCR2 binding assays, the orthosteric antagonist enhanced binding of the allosteric antagonist and structural analyses showed the orthosteric and allosteric antagonists bound the receptor via cooperative interactions with helix VII. Next steps include the identification and testing of allosteric inhibitors of other G protein-coupled chemokine receptors...