3P3R

Transthyretin in complex with (3,4-dihydroxy-5-nitrophenyl)(2-fluorophenyl)methanone


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.25 Å
  • R-Value Free: 0.180 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.156 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Potent kinetic stabilizers that prevent transthyretin-mediated cardiomyocyte proteotoxicity.

Alhamadsheh, M.M.Connelly, S.Cho, A.Reixach, N.Powers, E.T.Pan, D.W.Wilson, I.A.Kelly, J.W.Graef, I.A.

(2011) Sci Transl Med 3: 97ra81-97ra81

  • DOI: https://doi.org/10.1126/scitranslmed.3002473
  • Primary Citation of Related Structures:  
    3P3R, 3P3S, 3P3T, 3P3U

  • PubMed Abstract: 

    A valine-to-isoleucine mutation at position 122 of the serum protein transthyretin (TTR), found in 3 to 4% of African Americans, alters its stability, leading to amyloidogenesis and cardiomyopathy. In addition, 10 to 15% of individuals older than 65 years develop senile systemic amyloidosis and cardiac TTR deposits because of wild-type TTR amyloidogenesis. Although several drugs are in development, no approved therapies for TTR amyloid cardiomyopathy are yet available, so the identification of additional compounds that prevent amyloid-mediated cardiotoxicity is needed. To this aim, we developed a fluorescence polarization-based high-throughput screen and used it to identify several new chemical scaffolds that target TTR. These compounds were potent kinetic stabilizers of TTR and prevented TTR tetramer dissociation, partial unfolding, and aggregation of both wild type and the most common cardiomyopathy-associated TTR mutant, V122I-TTR. High-resolution co-crystal structures and characterization of the binding energetics revealed how these diverse structures bound to tetrameric TTR. These compounds effectively inhibited the proteotoxicity of V122I-TTR toward human cardiomyocytes. Several of these ligands stabilized TTR in human serum more effectively than diflunisal, which is a well-studied inhibitor of TTR aggregation, and may be promising leads for the treatment or prevention of TTR-mediated cardiomyopathy.


  • Organizational Affiliation

    Department of Pathology, Stanford University Medical School, Stanford, CA 94305, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Transthyretin
A, B
127Homo sapiensMutation(s): 0 
Gene Names: PALBTTR
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
3M1
Query on 3M1

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
(3,4-dihydroxy-5-nitrophenyl)(2-fluorophenyl)methanone
C13 H8 F N O5
RQPAUNZYTYHKHA-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3M1 PDBBind:  3P3R Kd: 56.05 (nM) from 1 assay(s)
BindingDB:  3P3R Kd: 184 (nM) from 1 assay(s)
IC50: 755 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.25 Å
  • R-Value Free: 0.180 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.156 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.848α = 90
b = 84.914β = 90
c = 64.35γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-08-24
    Type: Initial release
  • Version 1.1: 2013-01-09
    Changes: Database references
  • Version 1.2: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description