3TCP

Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC569


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.69 Å
  • R-Value Free: 0.298 
  • R-Value Work: 0.225 
  • R-Value Observed: 0.228 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of Novel Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia.

Liu, J.Yang, C.Simpson, C.Deryckere, D.Van Deusen, A.Miley, M.J.Kireev, D.Norris-Drouin, J.Sather, S.Hunter, D.Korboukh, V.K.Patel, H.S.Janzen, W.P.Machius, M.Johnson, G.L.Earp, H.S.Graham, D.K.Frye, S.V.Wang, X.

(2012) ACS Med Chem Lett 3: 129-134

  • DOI: https://doi.org/10.1021/ml200239k
  • Primary Citation of Related Structures:  
    3TCP

  • PubMed Abstract: 

    Ectopic Mer expression promotes pro-survival signaling and contributes to leukemogenesis and chemoresistance in childhood acute lymphoblastic leukemia (ALL). Consequently, Mer kinase inhibitors may promote leukemic cell death and further act as chemosensitizers increasing efficacy and reducing toxicities of current ALL regimens. We have applied a structure-based design approach to discover novel small molecule Mer kinase inhibitors. Several pyrazolopyrimidine derivatives effectively inhibit Mer kinase activity at sub-nanomolar concentrations. Furthermore, the lead compound shows a promising selectivity profile against a panel of 72 kinases and has excellent pharmacokinetic properties. We also describe the crystal structure of the complex between the lead compound and Mer, opening new opportunities for further optimization and new template design.


  • Organizational Affiliation

    Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase Mer
A, B
313Homo sapiensMutation(s): 0 
Gene Names: MERTKMER
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q12866 (Homo sapiens)
Explore Q12866 
Go to UniProtKB:  Q12866
PHAROS:  Q12866
GTEx:  ENSG00000153208 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ12866
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CKJ
Query on CKJ

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B]
1-[(trans-4-aminocyclohexyl)methyl]-N-butyl-3-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine
C22 H29 F N6
OGEBRHQLRGFBNV-RZDIXWSQSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
J [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
D [auth A],
H [auth B],
I [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
CKJ BindingDB:  3TCP Ki: 4.3 (nM) from 1 assay(s)
IC50: min: 2.9, max: 141 (nM) from 2 assay(s)
PDBBind:  3TCP Ki: 4.3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.69 Å
  • R-Value Free: 0.298 
  • R-Value Work: 0.225 
  • R-Value Observed: 0.228 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.158α = 90
b = 91.142β = 100.35
c = 68.356γ = 90
Software Package:
Software NamePurpose
PHASERphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-06-20
    Type: Initial release
  • Version 1.1: 2017-11-08
    Changes: Refinement description, Structure summary
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description