3CFQ

Crystal structure of human wild-type transthyretin in complex with diclofenac

Summary for 3CFQ

• Entry DOI: 10.2210/pdb3cfq/pdb
• Related: 1dvx 3CFM 3CFN 3CFT
• Descriptor: Transthyretin, 2-[2,6-DICHLOROPHENYL)AMINO]BENZENEACETIC ACID (3 entities in total)
• Functional Keywords: transthyretin, thyroxin, familial amyloid polyneurophaty, disease mutation, glycoprotein, hormone, polymorphism, polyneuropathy, retinol-binding, secreted, thyroid hormone, transport, vitamin a, transport protein
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted: P02766
• Total number of polymer chains: 2
• Total formula weight: 26515.32

Authors

Lima, L.-M.T.R.,Foguel, D.,Polikarpov, I. (deposition date: 2008-03-04, release date: 2009-03-03, Last modification date: 2023-08-30)

Primary citation

Lima, L.M.,Silva, V.D.,Palmieri, L.D.,Oliveira, M.C.,Foguel, D.,Polikarpov, I.
Identification of a novel ligand binding motif in the transthyretin channel.
Bioorg.Med.Chem., 18:100-110, 2010

PubMed Abstract: The design of therapeutic compounds targeting transthyretin (TTR) is challenging due to the low specificity of interaction in the hormone binding site. Such feature is highlighted by the interactions of TTR with diclofenac, a compound with high affinity for TTR, in two dissimilar modes, as evidenced by crystal structure of the complex. We report here structural analysis of the interactions of TTR with two small molecules, 1-amino-5-naphthalene sulfonate (1,5-AmNS) and 1-anilino-8-naphthalene sulfonate (1,8-ANS). Crystal structure of TTR:1,8-ANS complex reveals a peculiar interaction, through the stacking of the naphthalene ring between the side-chain of Lys15 and Leu17. The sulfonate moiety provides additional interaction with Lys15' and a water-mediated hydrogen bond with Thr119'. The uniqueness of this mode of ligand recognition is corroborated by the crystal structure of TTR in complex with the weak analogue 1,5-AmNS, the binding of which is driven mainly by hydrophobic partition and one electrostatic interaction between the sulfonate group and the Lys15. The ligand binding motif unraveled by 1,8-ANS may open new possibilities to treat TTR amyloid diseases by the elucidation of novel candidates for a more specific pharmacophoric pattern.

PubMed: 19954984
DOI: 10.1016/j.bmc.2009.11.025

Experimental method

X-RAY DIFFRACTION (2.09 Å)