Scientists have used macromolecular crystallography (MX) at Diamond to make a discovery that could pave the way for more effective, targeted drugs to treat inherited learning disabilities and other neurological diseases. UK-based Heptares Therapeutics, the pioneering structure-guided drug discovery and development company, has mapped the structure of a protein linked to the genetic disorder Fragile X Syndrome, a major cause of inherited learning disabilities, as well as to autism, depression, anxiety, addiction and movement disorders. Understanding the structure of this protein means a new generation of targeted medication could be fast on the heels of drugs currently undergoing clinical trials to treat the symptoms of these diseases.
Diamond Light Source produces a light 10 billion times brighter than the sun allowing scientists to study proteins at an atomic level. Using Diamond, Heptares scientists shone this intense light through pure protein crystals placed in the “beamline”, a specialist lab, and for the first time determined the 3D structure of the protein mGlu5 (metabotropic glutamate receptor 5), part of a family of receptors that controls brain activity. Heptares’ research, published today in the journal Nature, outlines a detailed understanding of mGlu5 and how it is affected by a drug which has been evaluated in clinical trials to treat Fragile X symptoms and other neurological disorders.
In the past, drug design has been largely the product of trial and error. Drugs would be developed and then tested until they had the desired effect. Because scientists lacked a comprehensive understanding of why and how the drugs were working, this approach could lead to unwanted side- effects.
Prof Andrew Harrison, Diamond's Chief Executive, comments, “Heptares is currently the biggest annual industrial user of Diamond. This is testament to our unique facilities and the success they have had in the past using techniques only available in the UK at Diamond. Whilst the majority of the research undertaken at Diamond is done by academia, currently 5% of the overall experimental time is purchased by 70 regular industry customers. They are using Diamond to advance R&D programmes across a range of sectors including pharmaceuticals, biotechnology, chemicals, oil and engineering. The synchrotron is playing a major role in keeping a strong R&D base in the UK and promoting highly advanced innovation within a range of businesses from British SMEs to global companies such as GSK and Rolls-Royce.”
Notes to EditorWhat is Fragile X Syndrome?
Fragile X Syndrome is one the leading known causes of inherited learning disabilities. It can cause a wide range of difficulties with learning, as well as social, language, attentional, emotional, and behavioural problems. Many children and adults also show autistic like features –and 5% of individuals with Fragile X Syndrome also have a dual diagnosis of autism. Fragile X Syndrome effectively “switches off” a protein that usually works in balance with mGlu5. Without its counterpart mGlu5 becomes overactive, sending too many signals in the brain, which impair function. Drugs designed to target mGlu5 would aim to stop this over-activity and reduce the symptoms caused by the imbalance.
Published in Nature online 6th July 2014
Andrew S. Doré et al. Structure of the class C GPCR metabotropic glutamate receptor 5 transmembrane domain, 2014, Nature http://dx.doi.org/10.1038/nature13396
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