Search Results

You searched for all publications:

with publication states 'Published' 'Published (Approved)'

Search Again...

These results include publications that have not yet been reviewed and processed by Diamond Light Source. To view only processed publications click here.

You can use the folder icon under Actions to collate papers as required. You can then click on View Folder in the left-hand navigation to review and/or download your folder.

Exact matches
Related results

2 items found (0 items not approved), displaying all items.1

Instruments / Technical Area	Publication Details	Published	Actions
I04-Macromolecular Crystallography	Trapping of palindromic ligands within native transthyretin prevents amyloid formation Simon E. Kolstoe , Palma P. Mangione , Vittorio Bellotti , Graham W. Taylor , Glenys A. Tennent , Stéphanie Deroo , Angus J. Morrison , Alexander J. A. Cobb , Anthony Coyne , Margaret Mccammon , Timothy D. Warner , Jane Mitchell , Raj Gill , Martin D. Smith , Steven Ley , Carol V. Robinson , Stephen P. Wood , Mark B. Pepys Proceedings Of The National Academy Of Sciences 107(47), 20483-20488 DOI: 10.1073/pnas.1008255107 PMID: 21059958 Open Access Show Abstract ▼ Abstract: Transthyretin (TTR) amyloidosis is a fatal disease for which new therapeutic approaches are urgently needed. We have designed two palindromic ligands, 2,2'-(4,4'-(heptane-1,7-diylbis(oxy))bis(3,5-dichloro-4,1-phenylene)) bis(azanediyl)dibenzoic acid (mds84) and 2,2'-(4,4'-(undecane-1,11-diylbis(oxy))bis(3,5-dichloro-4,1-phenylene)) bis(azanediyl)dibenzoic acid (4ajm15), that are rapidly bound by native wild-type TTR in whole serum and even more avidly by amyloidogenic TTR variants. One to one stoichiometry, demonstrable in solution and by MS, was confirmed by X-ray crystallographic analysis showing simultaneous occupation of both T4 binding sites in each tetrameric TTR molecule by the pair of ligand head groups. Ligand binding by native TTR was irreversible under physiological conditions, and it stabilized the tetrameric assembly and inhibited amyloidogenic aggregation more potently than other known ligands. These superstabilizers are orally bioavailable and exhibit low inhibitory activity against cyclooxygenase (COX). They offer a promising platform for development of drugs to treat and prevent TTR amyloidosis.	Nov 2010
I04-Macromolecular Crystallography	Targeting transthyretin - X-ray crystallography and rational drug design S. Kolstoe , A. Morrison , A. Cobb , A. Coyne , G. Gill , M. D. Smith , S. V. Ley , S. P. Wood , M. B. Pepys Amyloid 17 (s1), p102 DOI: 10.3109/13506121003737419 Show Abstract ▼ Abstract: Transthyretin (TTR) amyloid fibrillogenesis involves tetramer dissociation followed by structural changes within the monomer that render the protein capable of misassembly to the crossed-b form of the fibre. Kelly has pioneered a therapeutic strategy using small molecule ligands that bind in the thyroxine binding pockets of TTR to stabilise the native homotetrameric assembly. We designed palindromic, bivalent bis-aryl halides targeting the hormone binding sites of TTR to investigate the hypothesis that cross-linked octamers or higher multimers might experience enhanced clearance rates and provide a viable route for depleting this amyloidogenic protein from the circulation. As the compound 2-(3,5- dichlorophenyl amino)benzoic acid was reported to be bound by TTR with the chlorine bearing ring oriented to the outer halogen pockets of the protein, we linked two of these dichloro-bisaryl headgroups through their chlorinated rings with a 11 carbon linker. X-ray analysis of a co-crystallised complex with TTR revealed that this compound was bound simultaneously in both thyroxine binding sites of a single tetramer, with a complex translational disorder accommodating excess linker length and allowing both inner and outer halogen sites to be visited by the chlorine atoms of the ligand. X-ray analysis of an isolated head group bound by TTR showed that, in contrast to published data, such compounds are preferentially bound with their chlorinated rings located in the inner halogen pockets of the TTR tetramer. Structure analysis of a second bivalent compound in complex with TTR, where the linker length was reduced to seven carbon atoms, showed a well-ordered complex with the halogens of both head groups positioned in the inner sites of the TTR tetramer and clear electron density for the hydrocarbon linker passing through the centre of the tetramer. In contrast to previously reported studies of bivalent TTR ligands, this compound is rapidly bound by native TTR in solution and is a promising platform for development of drugs to inhibit TTR amyloid fibril formation in vivo.	Apr 2010

Publications Database

Search Results

You searched for all publications:

Search Again...

Subject Areas (check all that apply) select all

Instruments used to collect data (check all that apply) select all

Collaborations involved (check all that apply) select all

Diamond Offline Facilities used

Relevant Technical Areas (check all that apply) select all

Menu for Anonymous User