title: A new crystal form of human transthyretin obtained with a curcumin derived ligand.
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.
authors.affiliation: Synchrotron SOLEIL, l'Orme des Merisiers, Saint Aubin, BP 48, 91192 Gif-sur-Yvette, France; Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Polsinelli
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Nencetti
authors.affiliation: Synchrotron SOLEIL, l'Orme des Merisiers, Saint Aubin, BP 48, 91192 Gif-sur-Yvette, France.
authors.forename: William
authors.initials: W
authors.lastname: Shepard
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Ciccone
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Orlandini
authors.affiliation: Synchrotron SOLEIL, l'Orme des Merisiers, Saint Aubin, BP 48, 91192 Gif-sur-Yvette, France; CEA, iBiTec-S, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), Gif-sur-Yvette F-91191, France. Electronic address: estura@cea.fr.
authors.forename: Enrico A
authors.initials: EA
authors.lastname: Stura
mesh_terms: D001665:Binding Sites / Q000235:genetics; D047188:Chalcones / Q000737:chemistry / Q000378:metabolism; D003460:Crystallization; D018360:Crystallography, X-Ray; D003474:Curcumin / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011092:Polyethylene Glycols / Q000737:chemistry; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D055503:Protein Multimerization
chemical_list: D047188:Chalcones; D008024:Ligands; D011228:Prealbumin; C451019:4-hydroxychalcone; D011092:Polyethylene Glycols; D003474:Curcumin
keywords: Amyloidosis inhibition; Crystal packing; Crystal polymorphism; High pH transthyretin binding; Natural polyphenols; Transthyretin asymmetry