3V51

Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor RM-1-176


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.199 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Multiple Determinants for Selective Inhibition of Apicomplexan Calcium-Dependent Protein Kinase CDPK1.

Larson, E.T.Ojo, K.K.Murphy, R.C.Johnson, S.M.Zhang, Z.Kim, J.E.Leibly, D.J.Fox, A.M.Reid, M.C.Dale, E.J.Perera, B.G.Kim, J.Hewitt, S.N.Hol, W.G.Verlinde, C.L.Fan, E.Van Voorhis, W.C.Maly, D.J.Merritt, E.A.

(2012) J Med Chem 55: 2803-2810

  • DOI: https://doi.org/10.1021/jm201725v
  • Primary Citation of Related Structures:  
    3SX9, 3SXF, 3T3U, 3T3V, 3UPX, 3UPZ, 3UQF, 3UQG, 3V51, 3V5P, 3V5T

  • PubMed Abstract: 

    Diseases caused by the apicomplexan protozoans Toxoplasma gondii and Cryptosporidium parvum are a major health concern. The life cycle of these parasites is regulated by a family of calcium-dependent protein kinases (CDPKs) that have no direct homologues in the human host. Fortuitously, CDPK1 from both parasites contains a rare glycine gatekeeper residue adjacent to the ATP-binding pocket. This has allowed creation of a series of C3-substituted pyrazolopyrimidine compounds that are potent inhibitors selective for CDPK1 over a panel of human kinases. Here we demonstrate that selectivity is further enhanced by modification of the scaffold at the C1 position. The explanation for this unexpected result is provided by crystal structures of the inhibitors bound to CDPK1 and the human kinase c-SRC. Furthermore, the insight gained from these studies was applied to transform an alternative ATP-competitive scaffold lacking potency and selectivity for CDPK1 into a low nanomolar inhibitor of this enzyme with no activity against SRC.


  • Organizational Affiliation

    Department of Biochemistry, University of Washington, Seattle, Washington, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Calmodulin-domain protein kinase 1484Toxoplasma gondiiMutation(s): 0 
Gene Names: AAG53993CDPK1TGGT1_059880TGVEG_042030
EC: 2.7.11.17
UniProt
Find proteins for Q9BJF5 (Toxoplasma gondii)
Explore Q9BJF5 
Go to UniProtKB:  Q9BJF5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9BJF5
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
I76
Query on I76

Download Ideal Coordinates CCD File 
B [auth A]3-{6-[(3-chlorobenzyl)oxy]naphthalen-2-yl}-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
C25 H22 Cl N5 O
MGARWHQGMCYTAL-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
I76 PDBBind:  3V51 Ki: 2.8 (nM) from 1 assay(s)
BindingDB:  3V51 IC50: 5.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.199 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.317α = 90
b = 72.619β = 103.9
c = 67.356γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
Blu-Icedata collection
XSCALEdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-03-14
    Type: Initial release
  • Version 1.1: 2012-04-18
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations