Chemokine receptors are G Protein-Coupled Receptors (GPCRs) best known for their role in controlling cell migration in the context of immune system function. However, inappropriate regulation of chemokine-mediated processes contributes to the pathology of many diseases, the most validated of which is HIV where CCR5 and CXCR4, serve as co-receptors for viral entry into cells. Chemokines/receptors are also associated with a multitude of inflammatory diseases such as asthma, rheumatoid arthritis, and multiple sclerosis. For these reasons, they have become widespread targets in the pharmaceutical industry where high-resolution structures would be extremely valuable for drug design. In the last several years, structures of G Protein-Coupled Receptors (GPCRs) have finally succumbed to crystallization such that structures have been solved for ~25 different GPCRs including two chemokine receptors in complex with small molecule antagonists. However, the natural ligands of chemokine receptors are small proteins, and protein:protein complexes involving membrane proteins tend to be particularly challenging structural targets.  In this presentation I will describe our strategy for determining the structure of the chemokine receptor, CXCR4, in complex with a chemokine ligand and what we have learned from the structure.

Lessons from the structure of the chemokine receptor, CXCR4

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.