title: Nearly 200 X-ray crystal structures of transthyretin: what do they tell us about this protein and the design of drugs for TTR amyloidoses?
abstract: Transthyretin (TTR), a β-strand rich tetrameric protein present in human serum and cerebrospinal fluid is involved in the transport of thyroxine and retinol binding protein:retinol complex (holo-RBP). TTR forms two T4 binding sites at the center of the dimer-dimer interface and contains holo-RBP binding sites on both faces of the tetramer. Dissociation of TTR tetramers followed by misfolding and misassembly results in amyloid fibril formation, the causative agent of four neurodegenerative diseases. Misfolding of wild type TTR in humans over 60 years of age is linked to a sporadic amyloid disease called senile systemic amyloidosis. Single point mutations enhance the amyloidogenicity of TTR, causing familial amyloid cardiomyopathy, familial amyloid polyneuropathy, and central nervous system selective amyloidosis. To date, nearly 200 X-ray crystal structures of TTR and their complexes have been solved. They have provided potential insights into its structure-function relationships with molecular partners, and its interactions with small molecule ligands that inhibit tetramer destabilization and amyloid formation. This review will focus on the key findings of the structural studies of TTR that provided atomic level description of its architecture, the mechanistic role of structural components involved in its function and misfolding, and the progress and limitations towards the design of selective inhibitors for TTR amyloidoses.
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, 77843, USA. satheesh.palaninathan@gmail.com
authors.forename: S K
authors.initials: SK
authors.lastname: Palaninathan
mesh_terms: D000686:Amyloidosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding
chemical_list: D011228:Prealbumin