5U4G

Wild-type Transthyretin in complex with 2-Boronic Acid-1-[(1E)-2-(3-boronic acid)ethenyl]-4-chlorobenzene


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.191 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Stilbene Boronic Acids Form a Covalent Bond with Human Transthyretin and Inhibit Its Aggregation.

Smith, T.P.Windsor, I.W.Forest, K.T.Raines, R.T.

(2017) J Med Chem 60: 7820-7834

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b00952
  • Primary Citation of Related Structures:  
    5U48, 5U49, 5U4A, 5U4B, 5U4C, 5U4D, 5U4E, 5U4F, 5U4G

  • PubMed Abstract: 

    Transthyretin (TTR) is a homotetrameric protein. Its dissociation into monomers leads to the formation of fibrils that underlie human amyloidogenic diseases. The binding of small molecules to the thyroxin-binding sites in TTR stabilizes the homotetramer and attenuates TTR amyloidosis. Herein, we report on boronic acid-substituted stilbenes that limit TTR amyloidosis in vitro. Assays of affinity for TTR and inhibition of its tendency to form fibrils were coupled with X-ray crystallographic analysis of nine TTR·ligand complexes. The ensuing structure-function data led to a symmetrical diboronic acid that forms a boronic ester reversibly with serine 117. This diboronic acid inhibits fibril formation by both wild-type TTR and a common disease-related variant, V30M TTR, as effectively as does tafamidis, a small-molecule drug used to treat TTR-related amyloidosis in the clinic. These findings establish a new modality for covalent inhibition of fibril formation and illuminate a path for future optimization.


  • Organizational Affiliation

    Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Transthyretin
A, B
128Homo 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
7UV
Query on 7UV

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
(3-{(E)-2-[2-chloro-4-(hydroxyboranyl)phenyl]ethenyl}phenyl)boronic acid
C14 H13 B2 Cl O3
ZFFBGRNKFXBELR-SNAWJCMRSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.191 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.019α = 90
b = 85.118β = 90
c = 64.023γ = 90
Software Package:
Software NamePurpose
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
PHENIXrefinement
HKLdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesT32 GM008349
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesR01 GM044783
National Science Foundation (NSF, United States)United StatesMCB 1518160

Revision History  (Full details and data files)

  • Version 1.0: 2017-09-27
    Type: Initial release
  • Version 1.1: 2017-10-11
    Changes: Database references
  • Version 1.2: 2019-11-27
    Changes: Author supporting evidence, Derived calculations
  • Version 1.3: 2023-10-04
    Changes: Data collection, Database references, Refinement description