A new crystal form of human transthyretin obtained with a curcumin derived ligand

Journal of Structural Biology
Ivan PolsinelliEnrico A Stura

Abstract

Transthyretin (TTR), a 54kDa homotetrameric protein that transports thyroxine (T4), has been associated with clinical cases of TTR amyloidosis for its tendency to aggregate to form fibrils. Many ligands with a potential to inhibit fibril formation have been studied by X-ray crystallography in complex with TTR. Unfortunately, the ligand is often found in ambiguous electron density that is difficult to interpret. The ligand validation statistics suggest over-interpretation, even for the most active compounds like diflunisal. The primary technical reason is its position on a crystallographic 2-fold axis in the most common crystal form. Further investigations with the use of polyethylene glycol (PEG) to crystallize TTR complexes have resulted in a new trigonal polymorph with two tetramers in the asymmetric unit. The ligand used to obtain this new polymorph, 4-hydroxychalcone, is related to curcumin. Here we evaluate this crystal form to understand the contribution it may bring to the study of TTR ligands complexes, which are often asymmetric.

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Citations

Apr 14, 2016·Journal of Enzyme Inhibition and Medicinal Chemistry·Lidia CicconeElisabetta Orlandini
Jul 13, 2016·Journal of Structural Biology·Lidia CicconeWilliam Shepard
May 19, 2020·Journal of Enzyme Inhibition and Medicinal Chemistry·Lidia CicconeElisabetta Orlandini
Mar 17, 2019·International Journal of Molecular Sciences·Nelson FerreiraMaria Rosário Almeida
Sep 15, 2018·Scientific Reports·Lidia CicconeWilliam Shepard

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