Structure of key biological receptors solved by UK scientists

Scientists make receptor discoveries that pave the way for new drugs to treat metabolic diseases

The 2.5Å structure of the human glucagon receptor (GCGR) StaR complexed with the antagonist MK-0893 in sphere representation as viewed from a plane parallel to the membrane. MK-0893 (magenta) exhibits an extra-helical
binding mode from within the lipid bilayer clamping around Transmembrane helix 6.
Image courtesy of Andy Doré
The 2.5Å structure of the human glucagon receptor (GCGR) StaR complexed with the antagonist MK-0893 in sphere representation as viewed from a plane parallel to the membrane. MK-0893 (magenta) exhibits an extra-helical binding mode from within the lipid bilayer clamping around Transmembrane helix 6. Image courtesy of Andy Doré

New structural information obtained with the help of intense X-rays generated by Diamond Light Source, the UK’s synchrotron science facility in Oxfordshire, has enabled scientists from Heptares Therapeutics (“Heptares”, the UK-based subsidiary of Sosei Group Corporation) to solve the high-resolution X-ray crystal structure of the glucagon receptor. This biological receptor plays a crucial role in the management of blood glucose levels and is considered to be an important target for drugs designed to treat metabolic diseases, such as diabetes.

The breakthrough research by Heptares on this receptor, which was carried out on one of Diamond’s crystallography beamlines (I04), adds to the wealth of information the Company has generated using its StaR® platform on G protein-coupled receptors (GPCRs), the most important family of receptors targeted by drug developers. The unique resource, including detailed X-ray structures from more than 12 GPCRs solved by Heptares scientists, is enabling the Company to apply its structure-based design platform to develop therapeutics (small molecules and biologics) for these and structurally similar receptors that have strong links to disease.

Heptares is using the structural and physicochemical information derived from its pioneering research on the glucagon receptor, and from other receptors in the same class (Class B GPCRs), to advance small molecule GLP-1 antagonists towards the clinic as potential new treatments for the rare disease congenital hyperinsulinaemia.

The findings, published today in Nature by Heptares scientists, describe the identification of a novel binding site distinct from the glucagon-binding site. This ‘allosteric’ binding site is located outside the transmembrane domain of the receptor, at the interface with the cell membrane, and is shown to inhibit the normal signalling function of the receptor when bound to a small molecule antagonist MK-0893 (Jazayeri et al, reference below).

Prof Dave Stuart, Diamond’s Director of Life Sciences comments,

“This important research is a wonderful example of how industry is able to access Diamond’s advanced life science capabilities and contribute to the body of high impact papers that is helping researchers to advance drug development across a wide range of critical health areas. In particular, structural biology research is a key strength of Diamond and this research, pushing our understanding of GPCR binding modes, fully exploits our world leading facilities for macromolecular crystallography research. Additionally, in the past 12 months, we’ve extended our structural biology facilities to include cryo-electron microscopy and fragment screening, which moves us closer towards our vision of delivering a broad suite of capabilities that allows both academic and industrial researchers to tackle more challenging problems and progress their structural biology work further down the drug development pipeline.”

 

Fiona Marshall, Heptares
Fiona Marshall, Heptares

“Heptares continues to demonstrate the power of its StaR® technology to elucidate the structure of important GPCRs and apply this knowledge to its drug design programmes and those of it partners,” said Fiona Marshall, Chief Scientific Officer at Heptares.

“Our pioneering research is greatly enhancing our ability to apply our structure-based approach to drug discovery across a wide range of GPCR targets with strong clinical validation, but which have proved difficult or impossible to access previously. Access to Diamond’s crystallography beamlines remains critical for our work and the synchrotron’s developments in areas such as microfocus crystallography and membrane protein research will further strengthen the UK’s position as a leading contributor to structural biology research globally.”

Class B GPCRs represent a family of structurally similar receptors for peptide hormones such as GLP-1, glucagon, corticotropin-releasing factor (CRF), calcitonin and parathyroid peptide hormone. Class B GPCRs include many therapeutic targets for cardiovascular diseases, metabolic diseases, bone diseases and migraine, but despite strong clinical validation, structural information is limited. 

References

Jazayeri, A. et al (2016) Nature http://dx.doi.org/10.1038/nature17414

Hollenstein, K, et al Structure of class B GPCR corticotropin-releasing factor receptor 1. (2013) Nature 499: 438–443  doi: 10.1038/nature12357

About G-Protein Coupled Receptors

G-protein coupled receptors (GPCRs) are a large superfamily of integral membrane proteins that share a characteristic 7 transmembrane helix fold. They detect various molecules outside of the cell and signal their presence to the inside of the cell. At least half of the 800 human GPCRs are potential drug targets, so understanding their structure and function is critical.

Class B G protein-coupled receptors (GPCRs), also referred to as the secretin family of GPCRs, include receptors for a number of peptide hormones. These receptors are important drug targets in many human diseases including diabetes, osteoporosis, obesity, cancer, neurodegeneration, cardiovascular disease, headache and psychiatric disorders. However, the identification of small-molecule oral drugs for this family has proved extremely challenging. Extensive research by the pharmaceutical industry not been able to identify substances which mimic or block the large peptide ligands. An important reason for this is the lack of knowledge of the structure and location of sites that could bind drugs in class B GPCRs.

Structurally, class B GPCRs are made up of a large N-terminal extracellular domain (ECD) and a transmembrane domain (TMD) that includes the characteristic ‘GPCR’ signature of seven membrane spanning α-helices. It is this which is involved in facilitating information transfer across the cellular membrane in response to extracellular signals. 

Previous structural studies have greatly increased understanding of the molecular mechanisms of GPCR receptor ligand binding and activation and have enabled structure based approaches to drug design, but there has been difficulty in obtaining a structure of the TMD of any class B receptor, mainly due to the fact that GPCRs are owing to the inherent instability of these receptors and the limited availability of high-affinity small-molecule agonists and antagonists. 

 

Previous work by Heptares at Diamond

Scientists at Heptares unlock structure of elusive ‘stress’ protein