What Do Structures Tell Us About Chemokine Receptor Function and Antagonism?

Author:

Kufareva Irina1,Gustavsson Martin1,Zheng Yi1,Stephens Bryan S.1,Handel Tracy M.1

Affiliation:

1. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093;,

Abstract

Chemokines and their cell surface G protein–coupled receptors are critical for cell migration, not only in many fundamental biological processes but also in inflammatory diseases and cancer. Recent X-ray structures of two chemokines complexed with full-length receptors provided unprecedented insight into the atomic details of chemokine recognition and receptor activation, and computational modeling informed by new experiments leverages these insights to gain understanding of many more receptor:chemokine pairs. In parallel, chemokine receptor structures with small molecules reveal the complicated and diverse structural foundations of small molecule antagonism and allostery, highlight the inherent physicochemical challenges of receptor:chemokine interfaces, and suggest novel epitopes that can be exploited to overcome these challenges. The structures and models promote unique understanding of chemokine receptor biology, including the interpretation of two decades of experimental studies, and will undoubtedly assist future drug discovery endeavors.

Publisher

Annual Reviews

Subject

Cell Biology,Biochemistry,Bioengineering,Structural Biology,Biophysics

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