Shapeshifting receptors may explain mysterious drug failures | 4/15/2019 | Staff
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For sugar to taste sweet and for coffee to be stimulating, or even for light to be seen, first they all need to land on a G protein-coupled receptor. Ubiquitous and diverse, these receptors are a cell's chemical detection system: they sense substances in the surroundings and initiate intracellular pathways that underlie virtually all physiological processes—from taste and vision to hormonal regulation and neuronal communication. Nearly a third of all therapeutic drugs act by binding to these cell-surface receptors.

Yet finding more drug targets among this group has been difficult, and new research might explain why. Rockefeller scientists have found that many of these receptors, of which there are nearly 800, interact with so-called receptor activity–modifying proteins, or RAMPs, making them take up different configurations inside the body than in the lab.

Finding - Technique - Hundreds - Receptors - RAMPs

The finding was made possible by a new technique that can examine hundreds of receptors at once to reveal previously unknown RAMPs affecting their structure and function. Insights from this research, described in Science Advances, could have significant implications for drug discovery and help researchers understand a number of diseases.

Although widely studied, G protein-coupled receptors still prove elusive. Many drugs that successfully target them in preclinical studies ultimately fail in human trials. And for over a hundred of these receptors, scientists have not even been able to identify what hormone or protein in the body they bind to.

Hypothesis - Component - Thomas - P - Sakmar

"One hypothesis is that some component is missing," says Thomas P. Sakmar, the Richard M. and Isabel P. Furlaud Professor and head of Rockefeller's Laboratory of Chemical Biology and Signal Transduction. "That component could be the RAMP."

RAMPs were discovered serendipitously 20 years ago when a team of researchers working on a G protein coupled receptor, or GPCR, encountered a strange problem: the same receptor expressed in two different cell lines bound to different...
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