1UU3

Structure of human PDK1 kinase domain in complex with LY333531


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.174 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Interactions of Ly333531 and Other Bisindolyl Maleimide Inhibitors with Pdk1

Komander, D.Kular, G.S.Schuttelkopf, A.W.Deak, M.Prakash, K.R.Bain, J.Elliot, M.Garrido-Franco, M.Kozikowski, A.P.Alessi, D.R.Van Aalten, D.M.F.

(2004) Structure 12: 215

  • DOI: https://doi.org/10.1016/j.str.2004.01.005
  • Primary Citation of Related Structures:  
    1UU3, 1UU7, 1UU8, 1UU9, 1UVR

  • PubMed Abstract: 

    LY333531, BIM-1, BIM-2, BIM-3, and BIM-8 are bisindolyl maleimide-based, nanomolar protein kinase C inhibitors. LY333531, a PKCbeta-specific inhibitor, is in clinical trials against diabetes and cardiac ventricular hypertrophy complications. Specificity analysis with a panel of 29 protein kinases reveals that these bisindolyl maleimide inhibitors also inhibit PDK1, a key kinase from the insulin signaling pathway, albeit in the lower microM range. To understand the molecular basis of inhibition, the PDK1 kinase domain was cocrystallized with these bisindolyl maleimide inhibitors. The inhibitor complexes represent the first structural description of this class of compounds, revealing their unusual nonplanar conformation within the ATP binding site and also explaining the higher inhibitory potential of LY33331 compared to the BIM compounds toward PDK1. A combination of site-directed mutagenesis and essential dynamics analysis gives further insight into PDK1 and also PKC inhibition by these compounds, and may aid inhibitor design.


  • Organizational Affiliation

    Division of Biological Chemistry and Molecular Microbiology, University of Dundee, Dundee DD1 5EH, Scotland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
3-PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE-1310Homo sapiensMutation(s): 0 
EC: 2.7.1.37
UniProt & NIH Common Fund Data Resources
Find proteins for O15530 (Homo sapiens)
Explore O15530 
Go to UniProtKB:  O15530
PHAROS:  O15530
GTEx:  ENSG00000140992 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO15530
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
LY4
Query on LY4

Download Ideal Coordinates CCD File 
Q [auth A](9R)-9-[(DIMETHYLAMINO)METHYL]-6,7,10,11-TETRAHYDRO-9H,18H-5,21:12,17-DIMETHENODIBENZO[E,K]PYRROLO[3,4-H][1,4,13]OXADIA ZACYCLOHEXADECINE-18,20-DIONE
C28 H28 N4 O3
ZCBUQCWBWNUWSU-SFHVURJKSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
J [auth A]
K [auth A]
L [auth A]
M [auth A]
N [auth A]
J [auth A],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
O [auth A],
P [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
B [auth A]
C [auth A]
D [auth A]
E [auth A]
F [auth A]
B [auth A],
C [auth A],
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
A
L-PEPTIDE LINKINGC3 H8 N O6 PSER
Binding Affinity Annotations 
IDSourceBinding Affinity
LY4 BindingDB:  1UU3 Kd: 700 (nM) from 1 assay(s)
IC50: min: 500, max: 750 (nM) from 6 assay(s)
Binding MOAD:  1UU3 IC50: 750 (nM) from 1 assay(s)
PDBBind:  1UU3 IC50: 750 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.174 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 121.623α = 90
b = 121.623β = 90
c = 47.875γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2004-03-04
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2019-04-24
    Changes: Data collection, Derived calculations, Other, Source and taxonomy
  • Version 1.4: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description, Structure summary