Discovery of the Atomic Structure of a Ligand-Free G Protein-Coupled Receptor (GPCR) Will Help Design More Effective Drugs
The discovery, detailed in Nature Structural & Molecular Biology, shows the crystal structure of a GPCR -- the beta 1-adrenergic receptor -- that does not have a chemical signal or a "ligand" bound to it. The researchers say the finding will likely offer a major boost to drug development because designers can use information gleaned 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," says Dr. Xin-Yun Huang, a professor of physiology and biophysics at Weill Cornell Medical College.
"No one knew what a GPCR at its starting, basic unliganded state looked like -- or what to expect," he says. "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."
Mysterious Workings of GPCR Targeted Drugs
"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," says 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 says. Co-authors of the study are Jianyuan Huang, Shuai Chen, and J. Jillian Zhang, all from the Department of Physiology and Biophysics at Weill Cornell. The research was funded by a grant from the National Institutes of Health (HL 91525).
Weill Cornell Medical CollegeWeill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston.
For more information, visit weill.cornell.edu.
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