6PMA

TRK-A IN COMPLEX WITH LIGAND


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.53 Å
  • R-Value Free: 0.266 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.209 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Synthetic inhibitor leads of human tropomyosin receptor kinase A ( h TrkA).

Subramanian, G.Vairagoundar, R.Bowen, S.J.Roush, N.Zachary, T.Javens, C.Williams, T.Janssen, A.Gonzales, A.

(2020) RSC Med Chem 11: 370-377

  • DOI: https://doi.org/10.1039/c9md00554d
  • Primary Citation of Related Structures:  
    6PMA, 6PMB, 6PMC, 6PME

  • PubMed Abstract: 

    In silico virtual screening followed by in vitro biochemical, biophysical, and cellular screening resulted in the identification of distinctly different h TrkA kinase domain inhibitor scaffolds. X-ray structural analysis of representative inhibitors bound to h TrkA kinase domain defined the binding mode and rationalized the mechanism of action. Preliminary assessment of the sub-type selectivity against the closest h TrkB isoform, and early ADME guided the progression of select inhibitor leads in the screening cascade. The possibility of the actives sustaining to known h TrkA resistance mutations assessed in silico offers initial guidance into the required multiparametric lead optimization to arrive at a clinical candidate.


  • Organizational Affiliation

    Veterinary Medicine Research & Development , Zoetis , 333 Portage Street , Kalamazoo , MI 49007 , USA . Email: govindan.subramanian@zoetis.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
High affinity nerve growth factor receptor311Homo sapiensMutation(s): 0 
Gene Names: NTRK1MTCTRKTRKA
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P04629 (Homo sapiens)
Explore P04629 
Go to UniProtKB:  P04629
PHAROS:  P04629
GTEx:  ENSG00000198400 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04629
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
OQS (Subject of Investigation/LOI)
Query on OQS

Download Ideal Coordinates CCD File 
B [auth A]N-[2-chloro-5-(trifluoromethyl)phenyl]-2-[1-(4-methoxyphenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl]acetamide
C21 H15 Cl F3 N5 O3
VVMPLFOVCSRJQQ-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
A
L-PEPTIDE LINKINGC3 H8 N O6 PSER
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.53 Å
  • R-Value Free: 0.266 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.209 
  • Space Group: P 31 1 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 52.094α = 90
b = 52.094β = 90
c = 227.16γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
Aimlessdata scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2020-02-26
    Type: Initial release
  • Version 1.1: 2021-02-03
    Changes: Database references