LOS ANGELES — Researchers from City of Hope, one of the largest cancer research and treatment organizations in the United States, have identified how a protein receptor targeted by about 33% of all federally approved medication works. The discovery could facilitate pharmaceutical research because how and why this protein chooses to link to other proteins is critical to how cells will respond to medicines.
The recently published Nature Communications study, “Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity,” uncovered a cell signaling mechanism of the largest superfamily of drug target proteins, called G-protein coupled receptors. Located in the cell membrane, GPCRs bind to substances outside the cell, which in turn initiates coupling of GPCRs to G proteins, leading to biological changes in the cell. Mutations in GPCRs and G proteins have been implicated in cancer and diabetes.
“Using large-scale data analysis techniques, we have identified the rules of engagement of GPCRs with G proteins — or the ‘QR code’ for their coupling,” said Nagarajan Vaidehi, Ph.D., senior author of the study and chair of the Department of Computational and Quantitative Medicine at City of Hope. “Understanding the coupling mechanism of GPCRs to G proteins will aid in the design of drugs with lower side effects that target cancer-associated mutations.”
Researchers can use the QR code to design small molecule drugs that specifically affect the coupling of a target GPCR to a specific G protein. Such a drug will affect only the cell signaling pathways that are cancer-associated and leave the other pathways unaffected. This process would lead to cleaner and more targeted cancer therapies.
“We are using the QR code to identify more target-specific drugs,” Vaidehi said. “These findings are generalizable to any protein-to-protein coupling, which are emerging targets in personalized medicine,” Vaidehi said.
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The study was supported by the National Institutes of Health National Institute of General Medical Sciences (R01-GM117923, R01-GM097261), the UK Medical Research Council (MC_U105185859), the American Lebanese Syrian Associated Charities, the Lundbeck Foundation (R313-2019-526), the Novo Nordisk Foundation (NNF17OC003126), the Canadian Institute of Health Research (PJT-162368, PJT-173504).
About City of Hope
City of Hope's mission is to deliver the cures of tomorrow to the people who need them today. Founded in 1913, City of Hope has grown into one of the largest cancer research and treatment organizations in the U.S. and one of the leading research centers for diabetes and other life-threatening illnesses. As an independent, National Cancer Institute-designated comprehensive cancer center, City of Hope brings a uniquely integrated model to patients, spanning cancer care, research and development, academics and training, and innovation initiatives. Research and technology developed at City of Hope has been the basis for numerous breakthrough cancer medicines, as well as human synthetic insulin and monoclonal antibodies. A leader in bone marrow transplantation and immunotherapy, such as CAR T cell therapy, City of Hope’s personalized treatment protocols help advance cancer care throughout the world.
With a goal of expanding access to the latest discoveries and leading-edge care to more patients, families and communities, City of Hope’s growing national system includes its main Los Angeles campus, a network of clinical care locations across Southern California, a new cancer center in Orange County, California, and Cancer Treatment Centers of America. City of Hope’s affiliated family of organizations includes Translational Genomics Research Institute and AccessHopeTM. For more information about City of Hope, follow us on Facebook, Twitter, YouTube, Instagram and LinkedIn.
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Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity
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