Some proteins really know how to multitask. Some of the best are called G-protein coupled receptors, or GPCRs, for short.
New research by City of Hope scientists Nagarajan Vaidehi, Ph.D., and Supriyo Bhattacharya, Ph.D., shows how a single GPCR can have very different effects in a cell depending on the molecule that stimulates it. The scientists’ findings could help researchers create better targeted drugs with fewer side effects.
A protein supergroup
GPCRs comprise a superfamily of proteins involved in a wide range of biological processes including immunity, maintaining blood pressure, nerve cell activity and even cancer growth and spread.
These proteins bridge the cell membrane, with one section protruding up into the environment outside the cell, another dangling inside the cell and the middle anchored in the cell membrane. When a molecule, called a ligand, binds to the GPCR on the outer surface of the cell, the protein transmits the signal to the inside of the cell, and this sets off a cascade of biochemical events. This process is called cell signaling.
The signaling system is very specific, however. Each ligand interacts with a particular part of the GPCR outside the cell and only activates a certain corresponding biochemical cascade inside the cell.
The physics of biology
Vaidehi, a professor of immunology, and Bhattacharya, a staff scientist in Vaidehi’s lab, developed a way to understand how GPCRs communicate the message from outside the cell to the inside, and why different ligands set off distinct biochemical pathways.
“We developed a physics-based computational method that predicts the mechanism of cell signaling,” she said. Using known physical properties of the protein molecule, such as the size of different atoms and the electrical charges and their relative position within the protein, the researchers used high-powered computer algorithms to predict how the protein reacts when ligands bind to it.
They found that the protein changes shape slightly as atomic and molecular forces nudge its structure around. This shifting within the protein eventually leads to a change in a small part of the protein that hangs into the cell, and that change then sets off a corresponding biochemical cascade.
“Such transmission over relatively long distances within proteins is called ‘allosteric communication,’” said Vaidehi. “Our computational method maps allosteric communication pathways that GPCRs use.”
A need to be more 'biased'
Vaidehi and Bhattacharya are helping scientists design drugs that can target specific allosteric communication pathways. Called “biased drugs,” they target one signaling pathway and leave the rest untouched, minimizing side effects.
“Biased drugs are the new paradigm in drug design and the way to go, especially for diseases such as diabetes, hypertension or immune-related diseases where drugs are taken for a lifetime,” said Vaidehi.
Vaidehi and Bhattacharya are using this method in collaboration with scientists at Duke University, the University of California, San Diego, the University of California, San Francisco, Cambridge University in the United Kingdom and the National Institute of Neurological Disorders and Stroke in Washington, D.C.
A recognized breakthrough
This work is already getting attention from experts in the field, who see it as a breakthrough in understanding how GPCRs and similar proteins work. It also helps answer long-standing questions researchers have had about these signaling proteins. “This method has been used to rationalize the effect of several mutation experiments that were hitherto unexplained for 30 years,” Vaidehi said.
The study was recognized as “New and Notable” work by the Biophysical Journal and highlighted by F1000 Prime, an international group of experts that identifies and recommends important articles in biology and medical research.
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