Researchers have visualized the interaction between two critical components of the body's vast cellular communication network, a discovery that could lead to more effective medications with fewer side effects for conditions ranging from a migraine to cancer. The study was published in Cell.

The near-atomic resolution images, it shows a G-protein coupled receptor (GPCR) called rhodopsin bound to an inhibitory G protein and provides a blueprint for designing more precise, selective drugs while also solving a longstanding problem in the field.

Visualizing this complex resolves a missing chapter in the GPCR story by finally revealing how these two molecules interact in exquisite detail. Today's findings were made possible through the use of a revolutionary technique called cryo-electron microscopy (cryo-EM), which allows scientists to see tough-to-visualize molecules in startling clarity.

Cryo-EM Technology

The use of cryo-EM technology to obtain structural information on important pharmaceutical targets such as GPCRs in various states demonstrates that we are now in a position to apply these methods for drug discovery applications.

Embedded in the cell membrane, GPCRs act as conduits between a cell and its environment, interacting with G proteins and other signaling molecules called arrestins to convey important messages to and from the cell that regulate a gamut of physiological functions, including growth, immune responses, and sensory perception.

When linked up with GPCRs, inhibitory G proteins regulate the production of secondary chemical messengers that have effects throughout the body, 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, among many others.

These wide-ranging interactions with G proteins and arrestins, coupled with their accessibility on the outside of the cell, make GPCRs attractive targets for therapeutic development. Currently, more than 30% of medications on the market work by interacting with GPCRs.

They 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.

X-ray crystallography

GPCRs are notoriously difficult to visualize using traditional X-ray crystallography methods; to date, only 40 out of more than 800 total GPCRs have had their structures determined, including Xu's rhodopsin-arrestin complex.

To determine today's structure, the team harnessed VARI's high-powered Titan Krios cryo-electron microscope, which is capable of imaging molecules 1/10,000th the width of a human hair and can more easily visualize molecules like GPCRs that are embedded in the cell membrane. 

Researchers have pioneered the use of cryo-EM to determine some of the highest resolution structures reported so far using cryo-EM, including several clinically relevant ligand-protein complexes.