Proteins and peptides have a generic tendency to convert from their soluble states into well-organized aggregates characterized by a fibrillar morphology and an extended cross-beta structure. Such transitions can give rise to over 40 pathological conditions ranging from neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, polyQ disease, to systemic amyloidoses, including light chain amyloidosis and hemodyalisis-related amyloidosis. Unveiling the origins of amyloid disorders is one of the top scientific challenges. It is clear that a better understanding of the molecular mechanisms of protein and peptide aggregation into amyloid fibrils will allow optimal therapeutic strategies and the development of better drugs to combat these disorders. Nevertheless, despite the huge efforts of the scientific community, the molecular determinants underlying these processes are still largely obscure. The aim of the present project is to determine, at an atomic level, the structural and dynamical ensemble of the amyloidogenic intermediate of a novel Acilphosphatase, the AcPDro2. This protein represents a prototype of for studying the aggregation via native-like conditions, a major aggregation pathway in vivo. The project will be performed in the lab of prof. C.M. Dobson (University of Cambridge) and will be based on a multidisciplinary approach of experiments (basically solution-NMR) and molecular simulations to characterize the conformational ensembles adopted along the AcPDro2 aggregation pathway. This study will provide the atomic description of the molecular determinants of AcPDro2 aggregation into amyloid structures. Moreover, an appealing part of the project will focus on the mode of actions of a small ligand, the phosphate, which is able to inhibit the AcPDro2 aggregation. This determination will represent an unprecedented information with implications in the field of drug design for targeting amyloid-linked diseases.
Field of science
- /medical and health sciences/basic medicine/neurology/parkinson
- /natural sciences/biological sciences/biochemistry/biomolecules/proteins
- /medical and health sciences/basic medicine/neurology/alzheimer
Call for proposal
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