Crystalline reception: Classy membrane proteins

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  • Published: Aug 1, 2013
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Crystalline reception: Classy membrane proteins

Glucagon not forgotten

The crystal structure of the human glucagon receptor, found mainly in liver and kidney cells could provide researchers with an important target for therapeutic agents to treat type 2 diabetes. Scientists at The Scripps Research Institute (TSRI) leading an international team from the Chinese Academy of Sciences, the SLAC National Accelerator Laboratory and Novo Nordisk in Denmark, have now obtained the three-dimensional structure.

"Our data should change the current view of how drugs are designed with this and related receptors," explains TSRI's Fai Yiu Siu. GPCRs are the largest family of cellular receptors in humans and other animals targeted by more than a third of all modern pharmaceuticals. Finding ways to express, stabilize and induce these inherently flexible proteins to crystallise has been the focus of many research groups the world over. With the exception of the class F smoothened receptor, all of the GPCRs for which structures have been obtained so far have been "class A" GPCRs, the class B receptors GPCRs, which include the glucagon receptor as well as several closely related protein molecules.

Classy proteins

Class B receptors contain key functional domains embedded within and outside the cellular membrane, which distinguishes them from the class A group, making them even more intrinsically difficult to study. Other teams have reported the crystal structure data for the small soluble part of the glucagon receptor, the extracellular domain. However, the structure of the receptor's midsection, which is normally anchored in the host cell's membrane where the signal is transmitted, has remained elusive not least because it resists crystallization.

Siu used a technique borrowed from class A GPCR studies using a special fusion protein to hold the molecule together during crystallisation, which led to a 3.4 Angstrom resolution structure. The structure reveals an unusually elongated, stalk-like segment that connects the transmembrane region to the outermost, knob-like domain of the receptor, something not seen in class A receptors. A second feature is an unusually large pocket within the transmembrane region in which the N-terminal moiety of the glucagon peptide is thought to dock.

Insight and implication

The structural insight has implications for drug development and could assist pharmaceutical companies in their quest to target this receptor. "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," Siu explains. "Other than peptides, maybe the drugs need to be bigger and not conform to the usual characteristics of other drugs."

The team has also carried out studies of receptor mutants to characterise the glucagon-binding properties and how they change depending on amino acids from which a detailed model of how the full-length glucagon receptor operates has emerged. The outermost domain grabs one end of the glucagon peptide, then inserts the other end of the peptide into the large binding pocket in the transmembrane domain, locking the receptor structure in place and triggering receptor activation. The next step is to increase the resolution and to home in on the structure of the receptor with bound glucagon.

Related Links

Nature 2013, 499, 444–449: "Structure of the human glucagon class B G-protein-coupled receptor"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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