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August 3, 2000

Scientists map first structure in crucial family of proteins

An international team including scientists from the University of Washington has mapped the first crystal structure of a G protein-coupled receptor (GPCR), one of a family of proteins that are crucial to everything from vision to the development of the human embryo, according to a paper published in the Aug. 4 issue of Science.

A model of the protein is featured on the cover of the journal, which is published by the American Association for the Advancement of Science.

The particular GPCR that the scientists mapped is rhodopsin, a light receptor protein that resides inside cell membranes of retinal rod cells that carry out the first step in vision. It converts an environmental signal — light — into a biological action — a nerve signal to the brain. The process is called phototransduction. But GPCRs do more than this. They are one of the largest families of proteins encoded in the human genome, representing roughly 3 percent of the genome.

Work based on this model “should have far-reaching implications,” write Henry R. Bourne and Elaine C. Meng of the University of California, San Francisco, in an article accompanying the paper. “New insights gained will help us to understand how GPCRs transduce the signals that regulate embryonic development and control the heart, blood vessels, synaptic traffic in the brain and, indeed, the functions of virtually every eukaryotic cell.”

While genomes have been rightfully getting a lot of attention lately, the proteins that the genomes produce are what actually function inside the cell. For example, GPCRs are involved in the receptors found in the tongue — responsible for taste — and in the nose — responsible for detecting odors. Other GPCRs are involved in the regulation of the heartbeat. They are even found in the brain, in the opiate receptors that bind someone to a life of drug addiction. In other words, GPCRs participate in almost every physiological process.

“Because the underlying structure is similar, understanding one of these G protein-coupled receptors is important to understanding all of them. This first structure provides computational models that will guide us in future experiments to decipher how those other receptors work,” said the paper’s lead author, Dr. Krzystof Palczewski, Bishop professor of ophthalmology in the University of Washington School of Medicine. Dr. Tetsuji Okada, a postdoctoral fellow in Palczewski’s laboratory, initiated the project, working in darkness to crystallize the protein from bovine rod cells. The work had to be done in darkness because if the protein was exposed to light, it would change, just as it does in the human eye when exposed to light.

Other critical collaborators on this project include Dr. Ronald E. Stenkamp, UW associate professor of biological structure and Dr. Masashi Miyano of the Structural Biophysics Laboratory, Riken Harima Institute, in Riken, Japan. Both researchers and their laboratories were involved in sorting through 50 gigabytes of data to diagram the position of 348 amino acids in the crystal’s structure.

The title of the article is “Crystal Structure of Rhodopsin: A G Protein-Coupled Receptor.” Besides Palczewski, Stenkamp, Okada and Miyano, the authors include Takashi Kumasaka, Tetsuya Hori, Hiroyuki Motoshima, Masaki Yamamoto, (all of the Riken Institute) and Craig A. Behnke, Brian A. Fox, Isolde Le Trong and David C. Teller (all of the UW Biomolecular Structure Center).

Understanding the protein structure should help scientists who are trying to develop pharmacological treatments for many disorders, ranging from vision problems to drug addiction and depression, Palczewski says. For example, one well-known GPCR is a receptor responding to serotonin, which appears to play a significant role in mood.

GPCRs are one of the main targets of pharmacological interventions for many conditions. The paper’s authors hope that structural information about GPCRs may lead to significant advances in drug design, perhaps by better pinpointing ligands that can block or accelerate cell function. Besides being the first GPCR to be mapped, rhodopsin is now one of only about 10 membrane proteins that have been mapped to such detail. That’s because membrane proteins are not easily crystallized. Most proteins that have been analyzed so far are soluble, and reside inside a membrane.