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A Ray of Molecular Beauty from Cryo-EM

Posted on by Dr. Francis Collins


Credit: Subramaniam Lab, National Cancer Institute, NIH

Walk into a dark room, and it takes a minute to make out the objects, from the wallet on the table to the sleeping dog on the floor. But after a few seconds, our eyes are able to adjust and see in the near-dark, thanks to a protein called rhodopsin found at the surface of certain specialized cells in the retina, the thin, vision-initiating tissue that lines the back of the eye.

This illustration shows light-activating rhodopsin (orange). The light photons cause the activated form of rhodopsin to bind to its protein partner, transducin, made up of three subunits (green, yellow, and purple). The binding amplifies the visual signal, which then streams onward through the optic nerve for further processing in the brain—and the ability to avoid tripping over the dog.

The image comes from a paper published recently in Nature, in which a team of NIH scientists and grantees were able to capture for the first time the precise structural details of the rhodopsin-transducin interaction [1]. The research team was led by NIH’s Sriram Subramaniam, H. Eric Xu, Van Andel Research Institute, Grand Rapids, MI, and Anthony Kossiakiff, University of Chicago. They did it using cryo-electron microscopy (cryo-EM), a groundbreaking technique featured several times here on my blog.

While cryo-EM has helped to solve hundreds of new protein structures at high resolution in recent years, capturing the structure of activated rhodopsin bound to transducin took some major ingenuity. That’s because both proteins are extremely flexible. Even after they’ve been flash-frozen with liquid nitrogen, a key step in cryo-EM, it’s tough to get them to hold still in a particular conformation long enough to record their structure. The researchers ultimately pulled it off using a combination of sophisticated biochemistry and technical advances that allowed them to get even more detailed structural information out of the imaging data.

The team’s interest in rhodopsin goes far beyond its role in potentially blinding retinal degenerations, such as retinitis pigmentosa. Rhodopsin belongs to a group of proteins called G-protein coupled receptors (GPCRs). It is the largest and most diverse group of protein receptors in our bodies. In fact, more than a third of all approved medications act by binding to a GPCR protein [2].

What’s fascinating is the GPCRs respond to different messages, from light for rhodopsin to proteins and sugars for the other receptors. But all have key similarities. They share a common architecture and bind a relatively limited number of intracellular signaling proteins called G proteins.

For years, rhodopsin has served as an important structural model for understanding GPCRs. That includes those involved in regulating our appetites and our moods, via a class of G proteins known as inhibitory G proteins (Gi).

While researchers had solved the structure of a GPCR bound to another class of G proteins, known as stimulatory G proteins (Gs) in 2011[3], the image you see above represents the first such glimpse of a GPCR bound to any Gi protein. Subramaniam says this structure now serves as a critical starting point for researchers working to understand how many other molecular partners work together in many parts of our bodies. That’s good news for the future development of drugs designed to target those receptors ever more precisely, getting them to work better and with fewer side effects.


[1] Cryo-EM structure of human rhodopsin bound to an inhibitory G protein. Kang Y, Kuybeda O, de Waal PW, Mukherjee S, Van Eps N, Dutka P, Zhou XE, Bartesaghi A, Erramilli S, Morizumi T, Gu X, Yin Y, Liu P, Jiang Y, Meng X, Zhao G, Melcher K, Ernst OP, Kossiakoff AA, Subramaniam S, Xu HE. Nature. 2018 Jun;558(7711):553-558.

[2] G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs? Many Targe Sriram K, Insel PA. Mol Pharmacol. 2018 Apr;93(4):251-258.

[3] Crystal structure of the β2 adrenergic receptor-Gs protein complex. Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, Thian FS, Chae PS, Pardon E, Calinski D, Mathiesen JM, Shah ST, Lyons JA, Caffrey M, Gellman SH, Steyaert J, Skiniotis G, Weis WI, Sunahara RK, Kobilka BK. Nature. 2011 Jul 19;477(7366):549-55.


High Resolution Electron Microscopy (National Cancer Institute/NIH)

Xu Laboratory (Van Andel Research Institute, Grand Rapids, MI)

Kossiakiff Lab (University of Chicago)

Transformative High Resolution Cryo-Electron Microscopy Program (NIH Common Fund)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute

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