1Q8W

The Catalytic Subunit of cAMP-dependent Protein Kinase in Complex with Rho-kinase Inhibitor Fasudil (HA-1077)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.295 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.220 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Protein kinase A in complex with Rho-kinase inhibitors Y-27632, Fasudil, and H-1152P: structural basis of selectivity.

Breitenlechner, C.Gassel, M.Hidaka, H.Kinzel, V.Huber, R.Engh, R.A.Bossemeyer, D.

(2003) Structure 11: 1595-1607

  • DOI: https://doi.org/10.1016/j.str.2003.11.002
  • Primary Citation of Related Structures:  
    1Q8T, 1Q8U, 1Q8W

  • PubMed Abstract: 

    Protein kinases require strict inactivation to prevent spurious cellular signaling; overactivity can cause cancer or other diseases and necessitates selective inhibition for therapy. Rho-kinase is involved in such processes as tumor invasion, cell adhesion, smooth muscle contraction, and formation of focal adhesion fibers, as revealed using inhibitor Y-27632. Another Rho-kinase inhibitor, HA-1077 or Fasudil, is currently used in the treatment of cerebral vasospasm; the related nanomolar inhibitor H-1152P improves on its selectivity and potency. We have determined the crystal structures of HA-1077, H-1152P, and Y-27632 in complexes with protein kinase A (PKA) as a surrogate kinase to analyze Rho-kinase inhibitor binding properties. Features conserved between PKA and Rho-kinase are involved in the key binding interactions, while a combination of residues at the ATP binding pocket that are unique to Rho-kinase may explain the inhibitors' Rho-kinase selectivity. Further, a second H-1152P binding site potentially points toward PKA regulatory domain interaction modulators.


  • Organizational Affiliation

    Abteilung Strukturforschung, Max-Planck-Institut fuer Biochemie, 82152 Martinsried, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
cAMP-dependent protein kinase, alpha-catalytic subunit350Bos taurusMutation(s): 3 
Gene Names: PRKACA
EC: 2.7.1.37
UniProt
Find proteins for P00517 (Bos taurus)
Explore P00517 
Go to UniProtKB:  P00517
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00517
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
cAMP-dependent protein kinase inhibitor, alpha form20N/AMutation(s): 0 
UniProt
Find proteins for P61926 (Oryctolagus cuniculus)
Explore P61926 
Go to UniProtKB:  P61926
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP61926
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
M77
Query on M77

Download Ideal Coordinates CCD File 
C [auth A]5-(1,4-DIAZEPAN-1-SULFONYL)ISOQUINOLINE
C14 H17 N3 O2 S
NGOGFTYYXHNFQH-UHFFFAOYSA-N
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
A
L-PEPTIDE LINKINGC3 H8 N O6 PSER
TPO
Query on TPO
A
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Binding Affinity Annotations 
IDSourceBinding Affinity
M77 BindingDB:  1Q8W Ki: min: 460, max: 1600 (nM) from 2 assay(s)
IC50: min: 541, max: 7605 (nM) from 12 assay(s)
Binding MOAD:  1Q8W Kd: 5700 (nM) from 1 assay(s)
PDBBind:  1Q8W Kd: 5700 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.295 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.220 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 70.33α = 90
b = 73.67β = 90
c = 79.08γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
ASTROdata reduction
SAINTdata scaling
AMoREphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2003-12-16
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance