3CFN

Crystal structure of human transthyretin in complex with 1-anilino-8-naphthalene sulfonate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.87 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.203 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Identification of a novel ligand binding motif in the transthyretin channel.

Lima, L.M.Silva, V.D.Palmieri, L.D.Oliveira, M.C.Foguel, D.Polikarpov, I.

(2010) Bioorg Med Chem 18: 100-110

  • DOI: https://doi.org/10.1016/j.bmc.2009.11.025
  • Primary Citation of Related Structures:  
    3CFM, 3CFN, 3CFQ, 3CFT

  • PubMed Abstract: 

    The design of therapeutic compounds targeting transthyretin (TTR) is challenging due to the low specificity of interaction in the hormone binding site. Such feature is highlighted by the interactions of TTR with diclofenac, a compound with high affinity for TTR, in two dissimilar modes, as evidenced by crystal structure of the complex. We report here structural analysis of the interactions of TTR with two small molecules, 1-amino-5-naphthalene sulfonate (1,5-AmNS) and 1-anilino-8-naphthalene sulfonate (1,8-ANS). Crystal structure of TTR:1,8-ANS complex reveals a peculiar interaction, through the stacking of the naphthalene ring between the side-chain of Lys15 and Leu17. The sulfonate moiety provides additional interaction with Lys15' and a water-mediated hydrogen bond with Thr119'. The uniqueness of this mode of ligand recognition is corroborated by the crystal structure of TTR in complex with the weak analogue 1,5-AmNS, the binding of which is driven mainly by hydrophobic partition and one electrostatic interaction between the sulfonate group and the Lys15. The ligand binding motif unraveled by 1,8-ANS may open new possibilities to treat TTR amyloid diseases by the elucidation of novel candidates for a more specific pharmacophoric pattern.


  • Organizational Affiliation

    Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, RJ 21941-902, Brazil. mauricio@pharma.ufrj.br


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Transthyretin
A, B
118Homo 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
2AN
Query on 2AN

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
8-ANILINO-1-NAPHTHALENE SULFONATE
C16 H13 N O3 S
FWEOQOXTVHGIFQ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2AN Binding MOAD:  3CFN Kd: 4300 (nM) from 1 assay(s)
BindingDB:  3CFN Kd: min: 1100, max: 1.00e+4 (nM) from 5 assay(s)
PDBBind:  3CFN Kd: 1.00e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.87 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.203 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.296α = 90
b = 86.497β = 90
c = 63.463γ = 90
Software Package:
Software NamePurpose
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACTdata extraction
MAR345dtbdata collection

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-03-03
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.2: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description