LA JOLLA, CA---- A new approach to mapping how proteins interact with each other, developed at the Salk Institute for Biological Studies, could aid in the design of new drugs for diseases such as diabetes and osteoporosis. By reengineering proteins using artificial amino acids, the Salk scientists determine the detailed molecular structure of a cellular switch and its ligand, the molecule that turns it on. The switch--corticotrophin releasing factor type 1 (CRF1R)--belongs to a class of cellular receptors whose structures are notoriously hard to determine. These receptors regulate processes throughout the body and are involved in many diseases.
"Only when you know how the ligand binds to the receptor can you design drugs that target these processes," says senior study author Lei Wang, an associate professor in Salk's Jack H. Skirball Center for Chemical Biology and Proteomics and holder of the Frederick B. Rentschler Developmental Chair. Wang and his team describe the new structure and method in a Cell paper published online November 27.
Typically, researchers determine the three-dimensional arrangement of atoms in a protein molecule by crystalizing the protein and measuring how x-rays diffract off the crystals. But the receptor class the Salk scientists studied--known as class B G-protein coupled receptors (GPCRs)--are tricky to coax into crystal form, since they are only stable when embedded in the cellular membranes that enclose a cell's cytoplasm and nucleus. As a result, getting a complete picture of their structure--let alone the structure of the receptor combined with its bound ligand--hasn't been possible.
Wang's team turned to a new approach to try and figure out what CRF1R's binding pocket--the area where the ligand attaches--looked like. Using genetic engineering, the scientists added a unique new amino acid, one of the building blocks of proteins, to spots all along CRF1R.
"When you shine light o
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