4DET

Crystal Structure of the Wild Type TTR Binding Kaempferol (TTRwt:KAE)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.213 

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This is version 1.1 of the entry. See complete history


Literature

Flavonoid interactions with human transthyretin: Combined structural and thermodynamic analysis.

Trivella, D.B.Dos Reis, C.V.Lima, L.M.Foguel, D.Polikarpov, I.

(2012) J Struct Biol 180: 143-153

  • DOI: https://doi.org/10.1016/j.jsb.2012.07.008
  • Primary Citation of Related Structures:  
    4DER, 4DES, 4DET, 4DEU, 4DEW

  • PubMed Abstract: 

    Transthyretin (TTR) is a carrier protein involved in human amyloidosis. The development of small molecules that may act as TTR amyloid inhibitors is a promising strategy to treat these pathologies. Here we selected and characterized the interaction of flavonoids with the wild type and the V30M amyloidogenic mutant TTR. TTR acid aggregation was evaluated in vitro in the presence of the different flavonoids. The best TTR aggregation inhibitors were studied by Isothermal Titration Calorimetry (ITC) in order to reveal their thermodynamic signature of binding to TTRwt. Crystal structures of TTRwt in complex with the top binders were also obtained, enabling us to in depth inspect TTR interactions with these flavonoids. The results indicate that changing the number and position of hydroxyl groups attached to the flavonoid core strongly influence flavonoid recognition by TTR, either by changing ligand affinity or its mechanism of interaction with the two sites of TTR. We also compared the results obtained for TTRwt with the V30M mutant structure in the apo form, allowing us to pinpoint structural features that may facilitate or hamper ligand binding to the V30M mutant. Our data show that the TTRwt binding site is labile and, in particular, the central region of the cavity is sensible for the small differences in the ligands tested and can be influenced by the Met30 amyloidogenic mutation, therefore playing important roles in flavonoid binding affinity, mechanism and mutant protein ligand binding specificities.


  • Organizational Affiliation

    Instituto de Física de São Carlos, Universidade de São Paulo, 13560-970 São Carlos, SP, Brazil. danitrivella@iqm.unicamp.br


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Transthyretin
A, B
116Homo 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
KMP
Query on KMP

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
3,5,7-TRIHYDROXY-2-(4-HYDROXYPHENYL)-4H-CHROMEN-4-ONE
C15 H10 O6
IYRMWMYZSQPJKC-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
KMP PDBBind:  4DET Kd: 2100 (nM) from 1 assay(s)
Binding MOAD:  4DET Kd: 2100 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.213 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.326α = 90
b = 85.666β = 90
c = 64.35γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
MAR345dtbdata collection
HKL-2000data reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-11-21
    Type: Initial release
  • Version 1.1: 2024-02-28
    Changes: Data collection, Database references, Derived calculations