Heptares solves first X-ray structure of Family B GPCR, but full details not yet public
Sep17

Heptares solves first X-ray structure of Family B GPCR, but full details not yet public

In what might be the year's biggest molecular teaser, Heptares Therapeutics has announced that it has solved the first X-ray crystal structure of a G-protein coupled receptor in the Family B subclass. The work provides the first structural insights into a protein family that includes sought-after drug targets such as GLP-1 for diabetes and CGRP for migraine. Largely because of that drug discovery relevance, however, Heptares is choosing to keep its structure somewhat close to the vest. Officials presented views of the structure, of a GPCR called Corticotropin Releasing Factor (CRF-1) receptor, at conferences on Friday and Monday. But Heptares CEO Malcolm Weir says his team has no immediate plans to publish the structure or to deposit coordinates into the repository known as the Protein Data Bank. The structure, Weir says, is another success for Heptares' GPCR stabilizing technology, StaR. The technique involves targeted mutations that help to trap a GPCR in a single biologically-relevant state. In the case of CRF-1, Weir says, the stabilized receptor is captured in the "off" state. The structure itself, which is at a resolution of 3 Ångstroms, has the 7-helix membrane-spanning structure typical of GPCRs. However, CRF-1's architecture is rather different from receptors in Family A, the only GPCR family for which X-ray structures had been available until now, Weir says. "The overall shape of the receptor looks different, the orientation of the helices looks different, and there are detailed differences within helices that are at analogous positions in Family A receptors," he says. He notes that there are differences in helices 6 and 7, which undergo important motions during GPCR activation. "This is an important breakthrough, although fine details of the structure and release of coordinates may still be some time away," says Monash University's Patrick Sexton, an expert in Family B GPCRs who was at Friday's talk. The structure, he says, confirmed researchers' expectations that the major differences in membrane-spanning helices between Family A and Family B receptors would occur on the extracellular side. "There was a very open and relatively deep extracellular binding pocket, with the receptor having a 'V' shaped appearance," he says. This open pocket likely contributes to medicinal chemists' difficulties obtaining high affinity small molecule ligands for Family B receptors, he suggests. That open pocket might be involved in another Family B GPCR mystery, according to Roger Sunahara, also in attendance Friday, who studies GPCRs' molecular mechanisms at the University of Michigan, Ann Arbor. All Family B GPCRs, including CRF-1, have a large domain at their amino-terminus that contains large portions of their ligand binding sites. That domain was not included in this structure, he says, but...

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How Do You Get From Picture to Pill?
Jan26

How Do You Get From Picture to Pill?

Just about every time C&EN covers a newly-solved structure of a G-protein coupled receptor, we throw in a sentence about how the structure has big implications for drug discovery. And rightly so- G-protein coupled receptors (GPCRs) are one of the top types of proteins targeted by drugs. But just what does that statement mean? It's not like a medicinal chemist can look at that structure and instantly come up with a drug that controls the protein and treats a disease. I'm in Taos, New Mexico, at a Keystone Symposium called "Transmembrane Signaling by GPCRs and Channels", where I'm talking to researchers who take the information from pretty pictures of membrane-spanning proteins and use it to build viable drug candidates. Take a look at the Keystone Symposium's program, and you'll see a handful of speakers from industry. For instance, I've already heard a talk from Fiona Hamilton Marshall at Heptares Therapeutics and today (Wednesday) I will hear one from Kenneth E. Carlson at Anchor Therapeutics. I've also had the pleasure of meeting two folks who I've only spotted before on Twitter- Peter Nollert (@reducentropy) of Emerald Biosystems and UCSF postdoc Ryan G. Coleman (@rgcjk). This conference is already giving me more information than I can handle about solving GPCR structures- start drinking from the firehose with this overview of the tricks of the...

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