The research, led by the Institute of Biotechnology and Biomedicine of the Autonomous University of Barcelona (IBB-UAB) and the University of Washington in St. Louis, USA, focuses on the transthyretin (TTR) protein. Genetic mutations cause TTR to misfold and aggregate into amyloid fibers, leading to transthyretin amyloidosis (ATTR), a progressive and fatal disorder affecting the nervous system and vital organs.
While high-resolution studies using X-ray diffraction have determined over 300 TTR structures, they provide only a static image. Currently approved drugs offer generic activity and lack specific therapeutic responses for the diverse phenotypic variants of the disease, highlighting the urgent need to design new stabilizers tailored to specific mutations.
“"By applying mass spectrometry (MS) combined with two biochemical techniques, namely hydrogen-deuterium exchange (HDX) and fast photochemical oxidation of proteins (FPOP), we have been able to observe conformational changes induced by both mutations and ligand binding, which are invisible to X-ray crystallography."
This new methodological approach provides a dynamic view of the mechanism of action, comparable to a «movie» instead of a fixed image. This has allowed researchers to make important findings regarding the conformational changes caused by pathogenic TTR mutations and how stabilizing ligands counteract these effects.
“"We have revealed previously hidden destabilization mechanisms, opening up new ground for the design of specific stabilizers for each mutation, with significantly improved therapeutic potential. The design of new ligands should therefore consider the dynamic characteristics of each pathogenic TTR variant."
