Crystal Structure Obtained for Selectively Mutated G-Protein-Coupled Receptor

A team comprised of academics and researchers from the drug discovery industry have succeeded in obtaining the high-resolution crystal structure of a beta-1-adrenergic receptor, the G-protein-coupled receptor that regulates heart rate and blood pressure and is targeted by drugs commonly referred to as beta-blockers.

G-protein-coupled receptors (GPCRs) are a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses. GPCRs are only found in eukaryotes, including yeast, plants, and animals. The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins. GPCRs are involved in many diseases, but are also the target of around half of all modern medicinal drugs.

In order to work with the inherently instable GPCR, investigators at MRC Laboratory of Molecular Biology (Cambridge, UK) took advantage of recent developments made by the drug discovery company Heptares Therapeutics Ltd (London, UK). Heptares' proprietary StaR technology involves introducing a small number of point mutations into the structure of a GPCR to greatly improve its thermostability while preserving its functional and drug-binding characteristics. In this form, a StaR GPCR can be used for drug discovery approaches not previously applicable such as molecular modeling, solution phase assays, coupling to surfaces (chips), crystallization, and structure-based design.

The teamwork resulted in the publication in the June 25, 2008, online edition of the journal Nature of the 2.7-angstrom resolution crystal structure of a beta-1-adrenergic receptor in complex with the high-affinity antagonist cyanopindolol.

"The quality of the structural data we have been able to produce using this new approach is excellent and we feel the method is so robust there is no reason to think we would not be able to produce similar results with hundreds of other receptors. This will allow us to devise drugs that are much more selective for a single receptor,” said senior author Dr. Gebhard Schertler, a group leader at MRC Laboratory of Molecular Biology.

"This is a significant achievement by the MRC LMB team that validates the power and potential of our proprietary StaR technology for generating purified and functional GPCRs said Dr. Malcolm Weir, CEO of Heptares Therapeutics Ltd. "With this technology, we believe we have now overcome a significant problem that has severely limited application of contemporary drug discovery and antibody approaches to GPCRs because of their instability outside of their natural membrane environment. Given the importance of GPCRs in cell signaling and therefore as drug targets, this new technology has the potential to radically improve our understanding of the structure of GPCRs and in turn to develop better targeted drugs with fewer side effects.”


Related Links:
MRC Laboratory of Molecular Biology
Heptares Therapeutics Ltd