Using cryo-electron microscopy, a joint research group led by Dr. H. Eric Xu, a professor from Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences (CAS), have determined the structure of a molecular complex that is responsible for regulating vital physiological function. The study titled Cryo-EM structure of human rhodopsin bound to an inhibitory G protein, was published in the journal of Nature on 14th June, 2018.

G-protein-coupled receptors (GPCRs) constitute the largest family of transmembrane receptors targeted by ~34% approved drugs. They coupled to downstream signaling effectors, including the hetrotrimeric G proteins Gs (stimulatory), Gi (inhibitory) and several arrestin proteins, and mediate numerous cellular pathways.

When linked up with GPCRs, Gi regulate the production of secondary messengers from interactions with serotonin receptors in the brain and gut, which help regulate mood and appetite, to interactions with dopamine receptors in the brain, which control reward responses and voluntary movement.

The structural mechanisms that define how GPCRs selectively couple to a specific type of G protein or arrestin remain unknown. Recently, Dr. XU’s lab determined a near-atom resolution of cryo-EM structure of rhodopsin in complex with Gi.

For the first time, scientists have visualized the interaction between two critical components of the body’s vast cellular communication network. This is a discovery that could lead to more effective medications with fewer side effects for conditions ranging from migraine to cancer.

GPCRs are notoriously difficult to visualize using traditional X-ray crystallography. To date, only 40 out of more than 800 total GPCRs structures had been determined. The new findings were made through use of a revolutionary technique called cryo-electron microscopy (cryo-EM), which allows scientists to see tough-to-visualize molecules in startling clarity.

These findings are the latest in a series of firsts for Dr. XU and his team, which include a landmark 2015 Nature study that first described the structure of rhodopsin and arrestin in complex together. This work, as a major breakthrough in the field, earned Dr. XU the Hans Neurath Award from The Protein Society.

In a follow-up study published in Cell as cover story in 2017, Dr. XU and his collaborators further refined their earlier structure of the rhodopsin-arrestin complex, and revealed a set of phosphorylation codes that dictate the assembly of GPCR-arrestin complexes.

This study was a collaboration work conducted by researchers from SIMM, Van Andel Research Institute, Frederick National Laboratory for Cancer Research, University of Chicago, University of Toronto, Jagiellonian University, and the National Cancer Institute. Besides funds from international sources, this work was also supported by the National Science Foundation of China.

Article link: https://www.nature.com/articles/s41586-018-0215-y

High-resolution structure of Rhodopsin-arrestin complex. Orange, rhodopsin. Yellow, green and blue, heterotrimeric G-protein Gi. Purple, phospholipids in cell membrane(Image by Dr. XU’s lab)

Correspondence:
Dr. H. Eric Xu
Email: eric.xu@simm.ac.cn

(Credit: JIANG Yi; Editor: PAN Peihua)