Researchers at Massachusetts General Hospital (MGH) have solved the structure of an integrin receptor, a key protein involved in diseases and processes ranging from tumor angiogenesis and breast cancer metastasis to osteoporosis, vascular restenosis and foot-and-mouth disease. The finding, which will appear in Science magazine, was published Sept. 6 on the Science Express website http://www.
"Knowing the shape of this receptor will help us all develop strategies to target many of these diseases," says M. Amin Arnaout, MD, Director of the Structural Biology Program at MGH and Chief of the MGH Renal Unit. The other members of the MGH research team are Jian-Ping Xiong, PhD, Thilo Stehle, PhD, and David Scott, MD, PhD. The new information may be useful in designing novel anti-angiogenic, anti-inflammatory, anti-viral, and anti-osteoporosis drugs that target integrins.
The MGH team of researchers has been trying to decipher the three dimensional structure of this particular integrin receptor for several years. "This is the first look anyone has had at the whole structure of this class of receptors," says Arnaout.
Integrin receptors transmit chemical signals from a cell?s surface into its interior, which regulate most cellular processes such as attachment, proliferation, differentiation, and survival. Integrin receptors also have a unique ability to undergo shape-shifting as they become activated in response to the specialized needs of cells. "Elucidating the basic shape of these receptors is therefore key to understanding their function," says Arnaout.
An activated integrin receptor is able to bind a molecule called a ligand, in a lock and key fashion. Integrin receptors are very promiscuous, though, and they fit a variety of ligand 'keys,' including viral proteins that hijack these receptors to gain entry into cells.
There are many different types of integrin receptors, all with similar structural motifs. Some of these play important roles in other diseases, such as stroke, heart attack, diabetes, and rheumatoid arthritis. "This work will help researchers who are working on other integrin receptors to develop new therapeutic applications based on this work," says Arnaout.
The MGH team of researchers worked in collaboration with Merck KGaA in Germany and the Argonne National Laboratory in Illinois. The study was supported by research grants from the National Institutes of Health to the MGH team.
The Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $300 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, photo-medicine, transplantation biology. In 1994, the MGH joined with Brigham and Women?s Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and non acute and home health services.