News Release

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

Peer-Reviewed Publication

University of Maryland Biotechnology Institute

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 malfunctioning GPCR or mask the detrimental effects of such mutations," explains Ridge.

Rhodopsin is a well-studied GPCR model. Mutations in this light-sensing receptor lead to a variety of visual disorders that could well become an early target for the mimicking approach to help screen for drugs that block an aberrant function. Indeed, the best application of the technology, says Ridge, can be the development of an NMR-based drug screening approach for GPCRs.

"We took this engineered soluble mimic of rhodopsin and showed that it did essentially the same thing as the intact receptor," says Ridge. "So now we have something that is not only a functional mimic in terms of activating its G-protein, but it is also a structural mimic that induces the same conformational transition in the G-protein as the full-length, activated receptor. You don't need the membrane embedded portion of rhodopsin to study this interaction." It is thought that more than 1,000 genes in humans encode GPCRs.

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The scientific report can be found in Biochemistry, Vol. 42, No.2, 2003, by Ridge, J.P. Marino of CARB/NIST, N.G. Abdulaev of CARB/UMBI, and D.M Brabazon of Loyola College in Maryland.

The University of Maryland Biotechnology Institute was mandated by the state of Maryland legislature in 1985 as "a new paradigm of state economic development in biotech-related sciences." With five major research and education centers across Maryland, UMBI is dedicated to advancing the frontiers of biotechnology. The centers are the Center for Advanced Research in Biotechnology in Rockville; Center for Biosystems Research in College Park; and Center of Marine Biotechnology, Medical Biotechnology Center, and the Institute of Human Virology, all in Baltimore.


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