3IPE

Human Transthyretin (TTR) complexed with a palindromic bivalent amyloid inhibitor (7 carbon linker).


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.176 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Trapping of palindromic ligands within native transthyretin prevents amyloid formation.

Kolstoe, S.E.Mangione, P.P.Bellotti, V.Taylor, G.W.Tennent, G.A.Deroo, S.Morrison, A.J.Cobb, A.J.Coyne, A.McCammon, M.G.Warner, T.D.Mitchell, J.Gill, R.Smith, M.D.Ley, S.V.Robinson, C.V.Wood, S.P.Pepys, M.B.

(2010) Proc Natl Acad Sci U S A 107: 20483-20488

  • DOI: https://doi.org/10.1073/pnas.1008255107
  • Primary Citation of Related Structures:  
    3IPB, 3IPE, 3M1O

  • PubMed 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.


  • Organizational Affiliation

    Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London Medical School, London NW3 2PF, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Transthyretin
A, B
127Homo sapiensMutation(s): 0 
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
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
JZE
Query on JZE

Download Ideal Coordinates CCD File 
C [auth B]2,2'-{heptane-1,7-diylbis[oxy(3,5-dichlorobenzene-4,1-diyl)imino]}dibenzoic acid
C33 H30 Cl4 N2 O6
PVJQFPTYHVNSAO-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
JZE Binding MOAD:  3IPE IC50: 150 (nM) from 1 assay(s)
PDBBind:  3IPE IC50: 150 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.176 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.241α = 90
b = 84.876β = 90
c = 63.39γ = 90
Software Package:
Software NamePurpose
PHASERphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-11-17
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description