4HIS

The Structure of V122I Mutant Transthyretin in Complex with Tafamidis


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.172 
  • R-Value Work: 0.153 
  • R-Value Observed: 0.154 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin.

Penchala, S.C.Connelly, S.Wang, Y.Park, M.S.Zhao, L.Baranczak, A.Rappley, I.Vogel, H.Liedtke, M.Witteles, R.M.Powers, E.T.Reixach, N.Chan, W.K.Wilson, I.A.Kelly, J.W.Graef, I.A.Alhamadsheh, M.M.

(2013) Proc Natl Acad Sci U S A 110: 9992-9997

  • DOI: https://doi.org/10.1073/pnas.1300761110
  • Primary Citation of Related Structures:  
    4HIQ, 4HIS

  • PubMed Abstract: 

    The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidoses, which are most commonly caused by aggregation of Ig light chains or transthyretin (TTR) in the cardiac interstitium and conducting system, represent an important and often underdiagnosed cause of heart failure. Two types of TTR-associated amyloid cardiomyopathies are clinically important. The Val122Ile (V122I) mutation, which alters the kinetic stability of TTR and affects 3% to 4% of African American subjects, can lead to development of familial amyloid cardiomyopathy. In addition, aggregation of WT TTR in individuals older than age 65 y causes senile systemic amyloidosis. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. Here, we report the development of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of V122I-TTR in serum samples obtained from patients with familial amyloid cardiomyopathy. In contrast to other TTR stabilizers currently in clinical trials, AG10 stabilizes V122I- and WT-TTR equally well and also exceeds their efficacy to stabilize WT and mutant TTR in whole serum. Crystallographic studies of AG10 bound to V122I-TTR give valuable insights into how AG10 achieves such effective kinetic stabilization of TTR, which will also aid in designing better TTR stabilizers. The oral bioavailability of AG10, combined with additional desirable drug-like features, makes it a very promising candidate to treat TTR amyloid cardiomyopathy.


  • Organizational Affiliation

    Department of Pharmaceutics and Medicinal Chemistry, University of the Pacific, Stockton, CA 95211, USA.


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

Download Ideal Coordinates CCD File 
C [auth A]2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid
C14 H7 Cl2 N O3
TXEIIPDJKFWEEC-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3MI BindingDB:  4HIS Kd: min: 3, max: 2800 (nM) from 8 assay(s)
IC50: min: 1550, max: 3100 (nM) from 3 assay(s)
PDBBind:  4HIS Kd: 8.1 (nM) from 1 assay(s)
Binding MOAD:  4HIS Kd: 8.1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.172 
  • R-Value Work: 0.153 
  • R-Value Observed: 0.154 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.673α = 90
b = 84.601β = 90
c = 64.317γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
Blu-Icedata collection
autoXDSdata reduction
autoXDSdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-06-05
    Type: Initial release
  • Version 1.1: 2013-07-10
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description