November 5, 2007

Scientists Unveil Structure of Common Drug Target

Three-dimensional model of protein Crystal structure of the beta2-adrenergic receptor protein.Stevens Laboratory, The Scripps Research Institute.

More than 40 years after beta blockers were first used clinically, scientists have finally gotten a close-up look at the drugs' molecular target: the β2-adrenergic receptor. The breakthrough promises not only to speed the discovery of new and improved drugs, but to illuminate many aspects of human health and disease.

The β2-adrenergic receptor is one of a scientifically elusive family of proteins called G protein-coupled receptors (GPCRs). Membrane proteins such as GPCRs are notoriously tricky to capture in 3-dimensional detail. The only GPCR structure to be previously solved is the light-sensing protein rhodopsin, isolated from a cow's retina.

GPCRs span the cell membrane, bringing signals from outside the cell across the membrane so that the cell can react. They can be activated by a host of things, including hormones, light and small molecules. Once activated, GPCRs trigger a cascade of responses inside the cell. They control critical bodily functions, several of our senses and the action of about half of today's pharmaceuticals. They comprise the largest integral membrane protein family in the human genome, with over 1,000 members.

A research team led by Dr. Raymond Stevens of The Scripps Research Institute and Dr. Brian Kobilka of Stanford University reported in the October 25, 2007, online edition of Science that have they solved the structure of the human β2-adrenergic receptor. Their research was supported by 2 major NIH initiatives: the NIH Roadmap for Medical Research and the Protein Structure Initiative, which is led by NIH's National Institute of General Medical Sciences (NIGMS). Additional funding came from NIH's National Institute of Neurological Disorders and Stroke (NINDS).

This work represents a technical tour de force that required the scientists to devise several new techniques. To overcome problems with the protein's floppiness, for example, they replaced part of the protein to make it stiffer, essentially clamping it into place. They described their new methods in a separate companion paper in the same edition of the journal.

Dr. Jeremy M. Berg, director of NIGMS, said, "Many laboratories around the world are trying to reveal the secrets of these proteins and this new structure takes this field to a new level."

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