3FC8

Crystal structure of transthyretin in complex with iododiflunisal-betaAlaOMe


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Iodine atoms: a new molecular feature for the design of potent transthyretin fibrillogenesis inhibitors.

Mairal, T.Nieto, J.Pinto, M.Almeida, M.R.Gales, L.Ballesteros, A.Barluenga, J.Perez, J.J.Vazquez, J.T.Centeno, N.B.Saraiva, M.J.Damas, A.M.Planas, A.Arsequell, G.Valencia, G.

(2009) PLoS One 4: e4124-e4124

  • DOI: https://doi.org/10.1371/journal.pone.0004124
  • Primary Citation of Related Structures:  
    3FC8, 3FCB

  • PubMed Abstract: 

    The thyroid hormone and retinol transporter protein known as transthyretin (TTR) is in the origin of one of the 20 or so known amyloid diseases. TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites. The aggregation pathway of TTR into amiloid fibrils is not yet well characterized but in vitro binding of thyroid hormones and other small organic molecules to TTR binding channel results in tetramer stabilization which prevents amyloid formation in an extent which is proportional to the binding constant. Up to now, TTR aggregation inhibitors have been designed looking at various structural features of this binding channel others than its ability to host iodine atoms. In the present work, greatly improved inhibitors have been designed and tested by taking into account that thyroid hormones are unique in human biochemistry owing to the presence of multiple iodine atoms in their molecules which are probed to interact with specific halogen binding domains sitting at the TTR binding channel. The new TTR fibrillogenesis inhibitors are based on the diflunisal core structure because diflunisal is a registered salicylate drug with NSAID activity now undergoing clinical trials for TTR amyloid diseases. Biochemical and biophysical evidence confirms that iodine atoms can be an important design feature in the search for candidate drugs for TTR related amyloidosis.


  • Organizational Affiliation

    Unit of Glycoconjugate Chemistry, Institut de Química Avançada de Catalunya, I.Q.A.C.-C.S.I.C., Barcelona, Spain.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
transthyretin
A, B
124Homo sapiensMutation(s): 0 
Gene Names: TTRPALB
UniProt & NIH Common Fund Data Resources
Find proteins for P02766 (Homo sapiens)
Explore P02766 
Go to UniProtKB:  P02766
PHAROS:  P02766
GTEx:  ENSG00000118271 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP02766
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
IFA
Query on IFA

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
METHYL N-[(2',4'-DIFLUORO-4-HYDROXY-5-IODOBIPHENYL-3-YL)CARBONYL]-BETA-ALANINATE
C17 H14 F2 I N O4
ZMRRBWRMQPQQAN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
IFA Binding MOAD:  3FC8 IC50: 4100 (nM) from 1 assay(s)
PDBBind:  3FC8 IC50: 4100 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.196 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.238α = 90
b = 85.102β = 90
c = 63.064γ = 90
Software Package:
Software NamePurpose
DNAdata collection
PHASERphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-02-17
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-09-06
    Changes: Data collection, Database references, Refinement description