Understanding a cell's 'doorbell'

April 12, 2018, Los Alamos National Laboratory
Advancing the design of drugs for better medical effects takes a combination of experimental and computer simulation research. Scientists at Los Alamos National Laboratory, University of Toronto, Canada, University of California, San Diego and Kwansei Gakuin University, Japan are exploring how cellular components communicate with various nearby molecules. In this image, calcium bridges two parts of a cell receptor, possibly regulating its activity. Credit: Los Alamos National Laboratory

A multi-institutional project to understand one of the major targets of human drug design has produced new insights into how structural communication works in a cell component called a G protein-coupled receptor (GPCRs), basically a "doorbell" structure that alerts the cell of important molecules nearby. Understanding the structure and function of the receptor more deeply will enable better drug development.

"It's a huge field of active research in academia and industry because if we can figure out precisely how GPCRs work, then we can more easily design drugs to change their behavior and thereby control pain, hunger, and more," said coauthor Christopher Neale, a researcher with the Center for Nonlinear Studies at Los Alamos National Laboratory. "This work helps us in understanding the receptors' function as a means to enable future drug discovery. For instance, if calcium binding can turn off a GPCR, then one may use that knowledge in a guided search for drugs that either promote or inhibit calcium binding depending on the desired health outcome."

GPCRs are a family of membrane proteins that transmit information into our cells. They respond to things like adrenaline and opioid drugs, and they are the largest class of human targets. The research reported this week in Nature Communications describes the regulation of GPCRs by physiological ions such as sodium, calcium and magnesium.

The paper outlines in vitro experiments done by Scott Prosser's group (University of Toronto, Canada) that identified changes in these receptors based on divalent cation concentrations. The paper includes confirmation of these effects in live cells by Roger Sunahara's group (University of California, San Diego) and computer simulations run at Los Alamos by Neale and Angel E. Garcia to define atomic-resolution mechanisms that can explain the experimental results. Finally, additional theory by Adnan Sljoka (Kwansei Gakuin University, Japan) showed that the mechanisms that Neale proposed involve feasible types of structural communication through the receptor.

Explore further: New structure of key protein holds clues for better drug design

More information: Libin Ye et al, Mechanistic insights into allosteric regulation of the A2A adenosine G protein-coupled receptor by physiological cations, Nature Communications (2018). DOI: 10.1038/s41467-018-03314-9

Related Stories

Tracing water channels in cell surface receptors

September 9, 2014

G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors in our cells, involved in signal transmission across the cell membrane. One of the biggest questions is how a signal recognized at the extracellular ...

How receptors for medicines work inside cells

September 5, 2017

G protein-coupled receptors are the key target of a large number of drugs. W├╝rzburg scientists have now been able to show more precisely how these receptors act in the cell interior.

Distinct human mutations can alter the effect of medicine

December 18, 2017

Every person has a unique DNA sequence. Now, researchers from the University of Copenhagen and the MRC Laboratory of Molecular Biology in Cambridge have tried to quantify what these differences in the genome mean in the context ...

Recommended for you

Study reveals properties of a Type Ib supernova in NGC 4080

March 25, 2019

A recent study conducted by astronomers has revealed important observational properties of a Type Ib supernova designated MASTER OT J120451.50+265946.6, which exploded in the galaxy NGC 4080. The research, presented in a ...

Catalyst advance removes pollutants at low temperatures

March 25, 2019

Researchers at Washington State University, University of New Mexico, Eindhoven University of Technology, and Pacific Northwest National Laboratory have developed a catalyst that can both withstand high temperatures and convert ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.