Scientists from the University of Glasgow, Queen’s University Belfast and the University of Pittsburgh have mapped the atomic structure of a key protein receptor, revealing how it could be precisely targeted to treat metabolic diseases like diabetes, obesity and inflammatory conditions.
Published in Nature, the study offers new insight into FFA2 – a receptor influenced by gut-derived short-chain fatty acids – paving the way for more selective and effective therapies.
The researchers believe the new, detailed information on these protein complexes could greatly assist in the discovery of new treatments.
By harnessing and combining the power of structural biology, computational chemistry, pharmacology and cell signalling, the researchers looked at a receptor which is normally activated by the short chain fatty acids that are made by the fermentation of fibre in the diet by ‘good’ gut bacteria and which promote positive health outcomes – from the gut to the brain.
This receptor — FFA2 – is the primary receptor for short chain fatty acids in the body and because it is present in many immune cells, the pancreas, adipocytes and cells that generate hormones that control insulin levels and how full we feel, is a promising drug target for metabolic disorders including diabetes and obesity.
The researchers used three different chemical classes of synthetic ‘ligands’ identified by the pharmaceutical industry to activate this receptor and found each to work on FFA2 at different places.
The work led the researchers to demonstrate that each of these ligands makes short chain fatty acids function more effectively – but in different ways – allowing for the possibility of tuning this selectivity to improve pancreatic function and the roles of white blood immune cells, or control fat storage in adipose tissue.
Prof Graeme Milligan, Gardiner Chair of Biochemistry at the University of Glasgow’s School of Molecular Biosciences, said: “We are thrilled with our discoveries and believe this work could be extended to be applied across similar receptor proteins that are currently the molecular targets for 35% of clinically used medicines. These principles could have enormous reach and possibility in the world of drug discovery.”
Dr Irina Tikhonova from the School of Pharmacy at Queen’s University Belfast said: “Our molecular dynamics simulations using the Kelvin-2 supercomputer at Queen’s revealed how each compound uniquely changes the receptor’s shape, explaining their different signalling profiles. This computational approach was essential for connecting static structures with dynamic biological function.”
The study, ‘Allosteric modulation and biased signalling at free fatty acid receptor 2,’ is published in Nature. The study was supported by funding from the National Institutes of Health (NIH) in the USA, the Medical Research Council (UK), the Biotechnology and Biological Sciences Research Council (UK), the Lundbeck Foundation, and the EPSRC.