3ZH8

A novel small molecule aPKC inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.74 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.210 
  • R-Value Observed: 0.213 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Adenosine-Binding Motif Mimicry and Cellular Effects of a Thieno[2,3-D]Pyrimidine-Based Chemical Inhibitor of Atypical Protein Kinase C Isozymes.

Kjaer, S.Linch, M.Purkiss, A.Kostelecky, B.Knowles, P.P.Rosse, C.Riou, P.Soudy, C.Kaye, S.Patel, B.Soriano, E.Murray-Rust, J.Barton, C.Dillon, C.Roffey, J.Parker, P.J.Mcdonald, N.Q.

(2013) Biochem J 451: 329

  • DOI: https://doi.org/10.1042/BJ20121871
  • Primary Citation of Related Structures:  
    3ZH8

  • PubMed Abstract: 

    The aPKC [atypical PKC (protein kinase C)] isoforms ι and ζ play crucial roles in the formation and maintenance of cell polarity and represent attractive anti-oncogenic drug targets in Ras-dependent tumours. To date, few isoform-specific chemical biology tools are available to inhibit aPKC catalytic activity. In the present paper, we describe the identification and functional characterization of potent and selective thieno[2,3-d]pyrimidine-based chemical inhibitors of aPKCs. A crystal structure of human PKCι kinase domain bound to a representative compound, CRT0066854, reveals the basis for potent and selective chemical inhibition. Furthermore, CRT0066854 displaces a crucial Asn-Phe-Asp motif that is part of the adenosine-binding pocket and engages an acidic patch used by arginine-rich PKC substrates. We show that CRT0066854 inhibits the LLGL2 (lethal giant larvae 2) phosphorylation in cell lines and exhibits phenotypic effects in a range of cell-based assays. We conclude that this compound can be used as a chemical tool to modulate aPKC activity in vitro and in vivo and may guide the search for further aPKC-selective inhibitors.


  • Organizational Affiliation

    Structural Biology, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PROTEIN KINASE C IOTA TYPE
A, B, C
349Homo sapiensMutation(s): 1 
EC: 2.7.11.13
UniProt & NIH Common Fund Data Resources
Find proteins for P41743 (Homo sapiens)
Explore P41743 
Go to UniProtKB:  P41743
PHAROS:  P41743
GTEx:  ENSG00000163558 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP41743
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
C58
Query on C58

Download Ideal Coordinates CCD File 
BA [auth C],
I [auth A],
R [auth B]
(2S)-3-phenyl-N~1~-[2-(pyridin-4-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]propane-1,2-diamine
C24 H25 N5 S
NRHASZRDWOUMFD-SFHVURJKSA-N
IOD
Query on IOD

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
G [auth A]
M [auth B]
D [auth A],
E [auth A],
F [auth A],
G [auth A],
M [auth B],
N [auth B],
O [auth B],
P [auth B],
W [auth C],
X [auth C],
Y [auth C],
Z [auth C]
IODIDE ION
I
XMBWDFGMSWQBCA-UHFFFAOYSA-M
EDO
Query on EDO

Download Ideal Coordinates CCD File 
CA [auth C]
DA [auth C]
EA [auth C]
J [auth A]
K [auth A]
CA [auth C],
DA [auth C],
EA [auth C],
J [auth A],
K [auth A],
L [auth A],
S [auth B],
T [auth B],
U [auth B],
V [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
AA [auth C],
H [auth A],
Q [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
TPO
Query on TPO
A, B, C
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Binding Affinity Annotations 
IDSourceBinding Affinity
C58 PDBBind:  3ZH8 Kd: 341 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.74 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.210 
  • R-Value Observed: 0.213 
  • Space Group: P 31
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 113.58α = 90
b = 113.58β = 90
c = 82.41γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-02-27
    Type: Initial release
  • Version 1.1: 2013-04-17
    Changes: Database references
  • Version 1.2: 2019-04-03
    Changes: Data collection, Derived calculations, Other, Source and taxonomy
  • Version 1.3: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description