title: Screening transthyretin amyloid fibril inhibitors: characterization of novel multiprotein, multiligand complexes by mass spectrometry.
abstract: Tetrameric transthyretin is involved in transport of thyroxine and, through its interactions with retinol binding protein, vitamin A. Dissociation of these structures is widely accepted as the first step in the formation of transthyretin amyloid fibrils. Using a mass spectrometric approach, we have examined a series of 18 ligands proposed as inhibitors of this process. The ligands were evaluated for their ability to bind to and stabilize the tetrameric structure, their cooperativity in binding, and their ability to compete with the natural ligand thyroxine. The observation of a novel ten-component complex containing six protein subunits, two vitamin molecules, and two synthetic ligands allows us to conclude that ligand binding does not inhibit association of transthyretin with holo retinol binding protein.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, United Kingdom.
authors.forename: Margaret G
authors.initials: MG
authors.lastname: McCammon
authors.forename: David J
authors.initials: DJ
authors.lastname: Scott
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Keetch
authors.forename: Lesley H
authors.initials: LH
authors.lastname: Greene
authors.forename: Hans E
authors.initials: HE
authors.lastname: Purkey
authors.forename: H Michael
authors.initials: HM
authors.lastname: Petrassi
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
authors.forename: Carol V
authors.initials: CV
authors.lastname: Robinson
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D004353:Drug Evaluation, Preclinical; D008024:Ligands; D013058:Mass Spectrometry; D011108:Polymers; D011228:Prealbumin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism
chemical_list: D000682:Amyloid; D008024:Ligands; D011108:Polymers; D011228:Prealbumin; D014801:Vitamin A