'Mimics' may open screen(ing) door to GPCR drugs

ROCKVILLE, Md.- For starters, a team of scientists at the University of Maryland Biotechnology Institute and partners have engineered "soluble mimics" of rhodopsin, the light-sensing protein that lies deeply embedded in membranes of retina cells of the eye. Next, these mimics may open the door for drug designers to use x-rays, nuclear magnetic resonance (NMR), and other high-resolution structural tools to study the detailed workings of rhodopsin and other members of the superfamily of membrane proteins called G-protein coupled receptors (GPCRs).

In the journal Biochemistry, Kevin D. Ridge and co-authors describe a new approach for structurally characterizing functional regions of the rhodopsin protein that reside outside of the membrane. Assembly of these regions mimics how the receptor interacts with binding molecules called G-proteins. Ridge is a research chemist with UMBI's Center for Advanced Research in Biotechnology (CARB) and the National Institute of Standards and Technology (NIST).

GPCRs are very important to human health because they transmit and transform chemical signals from outside of cell to G-proteins inside the cell that mediate vision, smell, hearing, taste, and other processes. The GPCRs are already the targets of many therapeutic drugs for allergy, pain, hypertension, and other medical conditions.

GPCRs have been notoriously difficult to study at the structural level. They cross through the cell membrane seven times and any fault or mutation in the serpentine-like receptors may lead to a disease or illness. Ridge says engineering soluble mimics of these receptors may help medical researchers discover new drugs that target some of the consequences of these mutations.

Specifically, designing and characterizing "soluble mimics" of GPCRs could benefit structural approaches that are aimed at discovering more rationally designed drugs, possibly with fewer side effects, that could "block a mal

Contact: Steve Berberich
University of Maryland Biotechnology Institute

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