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by Bill Snyder | Monday, Dec. 2, 2013, 2:48 PM
Thanks in part to a computer program named “Rosetta,” Vanderbilt University researchers are closer to understanding how the ubiquitous G protein is activated – a discovery that could lead to the design of more specific and effective drugs.
“We always thought the G protein was like a stable rock,” said outgoing Pharmacology Chair Heidi Hamm, Ph.D. “But it’s not. It’s sitting there, right on the edge … (It’s) energetically poised to be activated by the receptor.”
The study provides a “really detailed energetic prediction of what is going on,” added Jens Meiler, Ph.D., co-senior author with Hamm of their report, published online this week in Nature Structural & Molecular Biology.
G proteins are intracellular “switches.” They are activated by membrane-bound receptors called G protein-coupled receptors, or GPCRs, through which hormones, neurotransmitters and more than half of all drugs on the market exert their effects.
GPCRs, however, can “turn on” multiple G protein-signaling pathways. Focusing on specific G protein-activated pathways inside the cell could lead to “laser-like” drugs with fewer side effects.
Rosetta was originally written by David Baker, Ph.D., head of the Institute for Protein Design at the University of Washington in Seattle. As a postdoctoral fellow in Baker’s lab, Meiler helped develop Rosetta algorithms that provide “energetic analyses” of protein-protein interactions.
Just as the Rosetta Stone provided the key to understanding Egyptian hieroglyphics, the Rosetta algorithm “was written to predict the protein structure from sequence, which is considered to be the Holy Grail in biology,” said Meiler, associate professor of Chemistry and Pharmacology who came to Vanderbilt in 2005.
“Now we use it for many different applications,” he said. “It goes to designing proteins that have a therapeutic function.”
Hamm, who returns to her lab full-time in January while a national search is conducted for her successor as chair, said the energetic analysis of the membrane receptor rhodopsin interacting with its G protein provides new insights into how G proteins are activated to transmit signals into the cell.
A previous paper published in 2011 by Hamm and her colleagues provided a “snapshot” of how the G protein “swings open” after binding to its G protein-coupled receptor or GPCR.The current study, led by first author Nathan Alexander, a former Chemistry graduate student in Meiler’s lab, “actually allows us to understand how each amino acid interacts with its environment,” added Hamm, who is internationally known for her contributions to understanding G protein-GPCR interactions.
By mutating specific amino acids, the researchers found they could affect the activation of the G protein.
The study not only provides a “roadmap for future experiments” to better understand G protein activation, it also could lead to more specific drugs with fewer side effects, drugs that “tweak” the activity of specific receptors, she said.
Hamm is the Aileen M. Lange and Annie Mary Lyle Professor of Cardiovascular Research, professor of Pharmacology, Ophthalmology &Visual Sciences and Orthopaedics & Rehabilitation.
Other co-authors were Anita M. Preininger, Ph.D., research assistant professor of Pharmacology, Pharmacology postdoctoral research fellow Ali Kaya, Ph.D., and Richard A. Stein, Ph.D., research instructor in Molecular Physiology and Biophysics.
The study was supported by National Institutes of Health grants GM080403, MH090192, GM099842, MH086222, EY006062 and GM084757.
Bill Snyder, (615) 322-4747
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