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3D Structure Solution of Critical Protein Could Help in Drug Discovery Efforts

By BiotechDaily International staff writers
Posted on 15 Apr 2013
Investigators have solved the three-dimensional (3D) crystal structure of a member protein in one of the most important classes of human proteins—the G protein-coupled receptors (GPCRs). These types of proteins latch on to and transmit chemical signals from outside the cell to the inside work by either inhibiting or activating GPCRs.

The discovery published February 2013 in the journal Nature Structural & Molecular Biology, revealed that the crystal structure of a GPCR, the beta 1-adrenergic receptor, does not have a chemical signal (ligand) bound to it. The researchers say the finding will likely offer a major boost to drug development because designers can use data gathered from the crystal structure to learn how to build new, more effective drugs.

“Now, by understanding the native structure of these receptors, which are likely very similar to each other, drug designers may be able to create therapies that are exquisitely targeted. That can produce better therapeutic results for patients while minimizing side effects,” said Dr. Xin-Yun Huang, a professor of physiology and biophysics at Weill Cornell Medical College (New York, NY, USA).

Scientists note that it was extremely difficult to crystallize this ligand-free membrane receptor, which clarified why no one has been able to unravel a GPCR structure without ligands previously, Dr. Huang added. One scientist who succeeded in solving the structures of several GPCRs bound to their ligands, and moreover, capture the structure of a GPCR bound to the G protein it typically activates on the inside of a cell, was awarded the 2012 Nobel Prize in Chemistry.

The atomic view of the unliganded GPCR has already offered some surprises to Dr. Huang and his investigators. “No one knew what a GPCR at its starting, basic unliganded state looked like—or what to expect,” he explained. “We found that the ligand-free beta 1-adrenergic receptors form oligomers. Identification of this structure type is important because it may provide the structural basis for the communication among receptors, and between receptors and G proteins.”

GPCRs are the largest group of cell surface receptors involved in signal transduction. They transmit signals from an enormous array of stimuli, everything from photons (light) to odorants, hormones, neurotransmitters, and growth factors, according to Dr. Huang, whose research has long narrowed in on the GPCRs and the G proteins they turn on inside a cell. The G proteins intensify and move the signal from GPCRs to produce a biochemical response.

This GPCR-G protein signaling system plays major roles in various physiologic mechanisms such as neurologic and cardiovascular functions, and in human diseases such as cancer. Drugs are designed to bind on the GPCRs and activate them, reduce their activity or turn their activity off. For example, the beta 1-adrenergic receptor on the outside of heart cells that Dr. Huang and his team crystallized is the target of beta-blocker drugs that slow down heartbeat.

Many agents that target GPCRs have been discovered by chance by screening large libraries of drug-like small molecules. Recently, crystal structures of GPCRs bound to ligands have helped researchers design new drugs. Drugs that fasten on to the same binding site on a GPCR may work to either activate or inhibit transmission of a signal. “It may be possible to compare the atomic structures of the ligand-free receptor in its starting state, when it is bound by a ligand that activates it and when it is bound by a ligand that inhibits it. The small differences may offer us clues to develop agents that elicit the reaction we want,” stated Dr. Huang.

Dr. Huang is now working to solve the 3D structure of the beta 1-adrenergic receptor linked to its partner G protein. “This may also provide a new template for designing new and more effective medications to control heart function,” he concluded.

Related Links:
Weill Cornell Medical College


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