Protein pocket could lead to new treatment for Fragile X

A pocket found in the structure of a protein linked to genetic disorder Fragile X Syndrome could herald a new generation of treatments for the condition. Metabotropic glutamate receptor 5 (mGlu5) is part of a family of receptors that controls brain activity and researchers have for the first time determined it’s 3D structure at an atomic level. Researchers shone an intense beam of light generated by a beamline at Diamond Light Source, through pure protein crystals of mGlu5. They identified a pocket in the structure which will allow the design of a drug which fits precisely into it. The work – published in Nature by Heptares Therapeutics, a UK-based structure-guided drug discovery and development company – has allowed a detailed understanding of the protein and how it is affected by drugs currently in clinical trials to treat Fragile X symptoms and other neurological disorders. The discovery could enable the development of a new generation of targeted medication for diseases linked to this family of proteins – including autism, depression and anxiety and movement disorders. These drugs would have improved effectiveness over those currently in development and would only affect the receptor with the pocket identified, reducing the chances of unwanted side effects. “Drugs currently in clinical trials could be on the market within about five years’ time, however, with the knowledge gathered in this study we could have a ‘new generation’ of precisely designed and more effective drugs within about ten years,” said Dr Fiona Marshall, Chief Scientific Officer at Heptares. “Being able to understand how the protein reacts to different drugs at an atomic level is invaluable in the success for research into these diseases.” Fragile X Syndrome is one of the leading known causes of inherited learning disabilities and can cause a wide range of difficulties with learning, social, language and attentional, emotional and behavioural problems. The Syndrome effectively switches off a protein that usually works with mGlu5, and without it, mGlu5 becomes overactive and sends too many signals to the brain, impairing function. Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain