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| The structure of the human glucagon receptor--Courtesy of Katya Kadyshevskaya, The Scripps Research Institute |
New research that unmasks the shape of a promising target for treating Type 2 diabetes could change the way scientists design drugs to regulate glucose in diabetics.
An international team led by scientists at The Scripps Research Institute in La Jolla, CA, has analyzed the three-dimensional atomic structure of the human glucagon receptor, a potential target for Type 2 diabetes found mainly on liver and kidney cells.
Human glucagon receptors are in the same class of receptors as "class B" G protein-coupled receptors. GPCRs are the largest family of cellular receptors in humans and other animals--with more than one-third of modern pharmaceuticals targeting these receptors--and all the ones whose structures are known to scientists are categorized as "class A" GPCRs. The class B GPCRs, including the glucagon receptor, have proved more challenging for scientists to solve.
Investigators identified the glucagon receptor and related GLP1 and GIP receptors as possible drug targets for diabetes because of their similarity to other receptors involved in endocrine and metabolic disorders.
The hormone glucagon becomes activated during fasting, triggering the release of stored glucose from the liver and other sites into the bloodstream. Scientists think that reining in the glucagon receptor's activity could offer a way to control blood sugar levels.
Scientists found that the structure of the glucagon receptor has two distinct characteristics that set it apart from class A GPCRs: an unusually elongated, stalklike segment that connects the transmembrane region to the outermost, knoblike domain of the receptor, and an unusually large "pocket" within the transmembrane region where the N-terminal part of the glucagon peptide is expected to dock.
"If you're trying to get a drug molecule to fit snugly into that pocket, you might need a larger one than those that are normally used to target class A GPCRs," said Scripps Research Associate Fai Yiu Siu, first author of the study, in a statement. "Other than peptides, maybe the drugs they're designing need to be bigger and not conform to the usual characteristics of other drugs."
With pharma companies already interested in GPCRs, the researchers believe their discovery could help guide future design of drugs for diabetes and other metabolic diseases.
- here's the press release
- and the study abstract