Scientists have determined the three-dimensional structure of a complete, unmodified G-protein-coupled receptor in its native environment: embedded in a membrane in physiological conditions. Using NMR spectroscopy, the team mapped the arrangement of atoms in a protein called CXCR1, which detects the inflammatory signal interleukin 8 and, through a G protein located inside the cell, triggers a cascade of events that can mobilize immune cells, for example. Because G-protein-coupled receptors are critical for many cellular responses to external signals, they have been a major target for drugs. More precise knowledge of the shapes of these receptors will allow drugmakers to tailor small molecules to better fit specific targets, avoiding collateral hits that can cause detrimental side effects. "This finding will have a major impact on structure-based drug development since for the first time the principal class of drug receptors can be studied in their biologically active forms where they interact with other proteins and potential drugs," said Dr. Stanley Opella, professor of chemistry and biochemistry at the University of California, San Diego, who led the work, which Nature published online on October 21, 2012, in advance of the print edition. Protein structures are most often determined by reading the diffraction patterns of X-rays beamed at their crystalline form, but crystallizing such large, unwieldy molecules is a challenge often met with strategies such as snipping off floppy ends. Those changes can alter the shape of critical regions of the protein. "Our approach was to not touch the protein," Dr. Opella said. "We are working with molecules in their active form." Their strategy has revealed a new view of these receptors. Previous reports have all noted seven helices weaving through the membrane.Login Or Register To Read Full Story