The Department of Biomedicine

BBB Seminar: Raymond C. Stevens

The incredible diversity of G-protein coupled receptors

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Raymond C. Stevens,
Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA, USA

G protein-coupled receptors (GPCRs) constitute one of the largest protein families in the human genome and play essential roles in normal cell processes, most notably in cell signaling. The human GPCR family contains of more than 800 members, recognizes thousands of different ligands and activates a number of signaling pathways through interactions with a small number of binding partners. After 20 years of technology innovation by researchers globally, the benefits of the technology efforts are now paying off, particularly in the area of understanding human GPCRs. Delivering GPCR structure-function data in close collaboration with the community on specific receptor systems is of immense value to the basic science community interested in cell signaling and molecular recognition, as well as the applied science community interested in drug discovery. To date, we have determined high resolution structures of 19 of the 30 (19 of the 21 human) GPCR structures available – notably the adrenergic, adenosine, angiotensin, chemokine, dopamine, glucagon, glutamate, histamine, lysophosphatidic, opioid, purinergic, serotonin, sphingolipid, and smoothened receptors, and representing class A, B, C and F receptor systems with new structures continuing to be deposited at a strong rate. Sadly, this coverage pales in comparison to the human kinase field with more than 230 novel structures out of ~500 human kinases. 

Crystallographic studies alone are only a part of the picture, and we have been following this work up with NMR, HDX, EM, and other biophysical techniques to understand the activation mechanism, including examining receptor-intracellular partner complexes such as the first view of the rhodopsin-arrestin complex structure. The use of the technology platform for drug discovery is now established through an industry-academia open source GPCR Consortium, Receptos, a small-molecule GPCR drug discovery company, and RuiYi, an antibody-GPCR company.

Chairperson: Aurora Martinez, Deptartment of Biomedicine