Computer artwork of a G protein-coupled receptor in the lipid bilayer of a plasma membraneMEDI-MATION LTD / PHOTO RESEARCHERSMembrane proteins represent only a handful of the total number of protein structures defined to date. Yet these proteins, which represent nearly 40 percent of all known proteins, including receptors, channels, and signaling molecules, are essential for cell communication and their malfunctions are implicated in many diseases. Structure-based design is one powerful way of developing drugs tuned to the precise actions and minimal side effects required for effective treatments. X-ray crystallography—still the only general method for solving the atomic structures of proteins of any size—has been hampered by the extreme difficulty of preparing and crystallizing pure membrane proteins.
The problem is a practical one: hydrophilic proteins, such as those in the cytoplasm, can form crystals in solution relatively easily, but membrane proteins also have hydrophobic parts that buoy the protein in the lipid layer. To maintain their shape, these lipid-loving domains must be surrounded by components that resemble the natural membrane—a requirement that makes it difficult to grow well-diffracting crystals. However, an array of technical advances over the last 2 years has advanced our ability to determine these structures.
Advances are the result of developments at multiple steps in the crystallization process. One example comes from Raymond Stevens and colleagues at the Scripps Research Institute who discovered that lipids were essential for determining the structure of a G protein-coupled receptor (GPCR) that responds ...
