4AT5

CRYSTAL STRUCTURE OF TRKB KINASE DOMAIN IN COMPLEX WITH GW2580


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.71 Å
  • R-Value Free: 0.186 
  • R-Value Work: 0.158 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

The Crystal Structures of Trka and Trkb Suggest Key Regions for Achieving Selective Inhibition.

Bertrand, T.Kothe, M.Liu, J.Dupuy, A.Rak, A.Berne, P.F.Davis, S.Gladysheva, T.Valtre, C.Crenne, J.Y.Mathieu, M.

(2012) J Mol Biol 423: 439

  • DOI: https://doi.org/10.1016/j.jmb.2012.08.002
  • Primary Citation of Related Structures:  
    4ASZ, 4AT3, 4AT4, 4AT5, 4F0I

  • PubMed Abstract: 

    The Trk family of neurotrophin receptors, which includes the three highly homologous proteins TrkA, TrkB and TrkC, is strongly associated with central and peripheral nervous system processes. Trk proteins are also of interest in oncology, since Trk activation has been observed in several cancer types. While Trk kinases are attractive oncology targets, selectivity might be more of an issue than for other kinases due to potential CNS side effects if several Trk kinases are simultaneously targeted. In order to address this issue, we present here the first structures of human TrkA and TrkB kinase domains and three complexes between TrkB and Trk inhibitors. These structures reveal different conformations of the kinase domain and suggest new regions of selectivity among the Trk family.


  • Organizational Affiliation

    Department of Structure, Design, and Informatics, Sanofi, 13 Quai Jules Guesde, Vitry-sur-Seine, 94403 Cedex, France. thomas.bertrand@sanofi.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BDNF/NT-3 GROWTH FACTORS RECEPTOR299Homo sapiensMutation(s): 0 
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q16620 (Homo sapiens)
Explore Q16620 
Go to UniProtKB:  Q16620
PHAROS:  Q16620
GTEx:  ENSG00000148053 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ16620
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MUJ
Query on MUJ

Download Ideal Coordinates CCD File 
B [auth A]5-{3-methoxy-4-[(4-methoxybenzyl)oxy]benzyl}pyrimidine-2,4-diamine
C20 H22 N4 O3
MYQAUKPBNJWPIE-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
C [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
MUJ BindingDB:  4AT5 Kd: 36 (nM) from 1 assay(s)
PDBBind:  4AT5 IC50: 38 (nM) from 1 assay(s)
Binding MOAD:  4AT5 IC50: 38 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.71 Å
  • R-Value Free: 0.186 
  • R-Value Work: 0.158 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 88.54α = 90
b = 94.19β = 90
c = 46.32γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-08-22
    Type: Initial release
  • Version 1.1: 2012-10-10
    Changes: Database references
  • Version 1.2: 2013-07-24
    Changes: Refinement description
  • Version 1.3: 2019-04-03
    Changes: Data collection, Experimental preparation, Other
  • Version 1.4: 2019-04-24
    Changes: Data collection, Source and taxonomy
  • Version 1.5: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description