Protein dynamics: NMR focuses on GPCRs

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  • Published: Jan 5, 2018
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Protein dynamics: NMR focuses on GPCRs

Key proteins

Probes (shown glowing here) revealed the inner architecture of the protein A2aAR in the new study. Credit: Kurt Wuthrich and Matthew Eddy, The Scripps Research Institute

Nuclear magnetic resonance (NMR) spectroscopy has allowed US researchers to peer into the heart of a key protein used in drug design to reveal dynamic structural features that may lead to new ways for targeting disease.

Matthew Eddy, Kurt Wüthrich, Tatiana Didenko, Pawel Stanczak, and Reto Horst of The Scripps Research Institute together with Zhan-Guo Gao and Kenneth Jacobson of the National Institutes of Health, and Ming-Yue Lee, Kyle McClary, Gye Won Han, Martin Audet, Kate White, and Raymond Stevens of the University of Southern California have looked closely at A2A adenosine receptor (A2aAR), a member of the G-protein-coupled receptor (GPCR) family of proteins. This group represents a large family of proteins addressed by two in every five approved pharmaceuticals. The team's detailed image of the protein's signalling mechanism reveals more about its mode of action than was known previously. It also shows that one an amino acid in its sequence acts as a toggle switch to control signalling across the cell membrane.

"This basic knowledge is potentially helpful for improving drug design," explains Wüthrich. The team published details in the journal Cell in December.

Dynamic membrane

All of our cells contain A2aAR and other GPCRs embedded in their plasma membrane. There are more than 800 known GPCRs and each is thought to have a role in regulating a specific function. For example, A2aAR itself regulates blood flow and inflammation and also mediates the effects of certain exogenous compounds a person might ingest, such as the caffeine from coffee. The same protein has also been verified as a target for drugs that might be used to treat the debilitating and ultimately fatal Parkinson’s disease as well as offering hope as a fairly new target for anticancer drugs.

“GPCRs do just about everything you can imagine,” explains Wüthrich. “But for a long time, drug design was being done without knowing how GPCRs looked.” This new study changes all of that. In the new work, the scientists wanted to reveal more detail about the relationship between the function of A2aAR and the dynamic changes in its structure it undergoes when it is active, such insights would help in the design of novel pharmaceutical agents for a range of conditions, including those mentioned above.


The research builds on earlier based on X-ray crystallography. That work showed that A2aAR resembles a chain that crisscrosses the cell membrane and has an opening on the side facing out of the cell. The region of the GPCR structure that sticks out of the membrane is the portion that interacts with drugs and other molecules that impinge in it and signal to partner proteins within the cell itself.

While the crystal structures have provided key details of the receptor’s shape in both its inactive and active state, their very nature means that they cannot reveal motion and dynamics in the protein in its native state in the membrane. NMR spectroscopy, of course, does not require the analyte to be crystalline and so can be used to track such molecular dynamics. Indeed, Wüthrich is a world-renowned leader in this area and recipient of the 2002 Nobel Prize in Chemistry for his pioneering work.

Eddy has now used NMR spectroscopy to study A2aAR in various different conformations and his data shed a little light on how the protein changes conformation on the surface of human cells in response to interaction with drug molecules. Importantly, the data reveal much about the internal architecture of A2aAR, which takes the science a large step beyond previous solution NMR studies. Those earlier studies had focused on the technically less demanding observation of NMR-observable probes attached to flexible parts of GPCRs, which were generally located at or near the surface of the receptor. The new approach taken by Eddy and colleagues enabled them to follow the effects of drug binding at the extracellular surface on changes in protein structure and dynamics at the intracellular surface. This is the structural basis of signal transfer and so offers vital clues to the behaviour of the GPCR.

Related Links

Cell 2017, online: "Allosteric Coupling of Drug Binding and Intracellular Signaling in the A 2A Adenosine Receptor"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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