Unlocking the structure of elusive stress receptor

A spin-out pharmaceutical company has visualised for the first time a complicated protein receptor in the brain which controls our response to stress.

Heptares Therapeutics, formed by a Cambridge molecular biology group, used beam-time at Diamond Light Source, the UK’s synchrotron facility in Oxfordshire, to identify the three dimensional structure of a receptor named corticotropin-releasing factor 1 (CRF1). Their findings are published in Nature.

Professor David Stuart, Life Science director of Diamond Light Source told Laboratory News: “CRF1 belongs to a family of receptors called GPCRs. GPCRs account for 30% of current drug targets. Within the GPCR family, CRF1 belongs to class B. Class B receptors tend to be activated in many diseases such as diabetes and osteoporosis. There’s a real need for pharmaceutical modulation of these receptors, but up until this point, there’s been no structural information, so designing drugs that target this receptor has been tricky.”

Scientists at Heptares had a novel idea to alter proteins found in cell membranes in order to make crystals of them. In this crystalised state, the stress protein receptor is able to be visualised at the atomic level.

However, the level of detail required for this work could only be achieved using the intense synchrotron light produced at Diamond Light Source. The synchrotron there speeds electrons to near light speed, producing a beam 10 billion times brighter than the sun.

“The devil is in the detail. A rough structural model is useless in terms of understanding functional biology and that’s why the resolution provided by the synchrotron at Diamond Light Source is key,” said Stuart.

So after freezing the receptor crystals in liquid nitrogen, the Heptares team took them to Diamond. By visualising the stress protein receptor, they were able to identify, for the first time, a ‘pocket’ in the structure. Computer technology will allow scientists to begin designing drugs that can precisely target the pocket to modulate the stress receptor’s response

Fiona Marshall, Chief Scientific Officer at Heptares said: “Publishing this research in Nature will get this family of protein receptors on the radar of the drug discovery and development industry and help facilitate the design of some important new drug treatments. Here at Heptares, we are applying this structural knowledge to a related protein called GLP1 to enable us to develop an oral tablet for controlling glycaemia and reducing weight in patients with Type 2 diabetes. Diamond will continue to play an important role in our future research.”