3V8S

Human RHO-ASSOCIATED PROTEIN KINASE 1 (ROCK 1) IN COMPLEX WITH INDAZOLE DERIVATIVE (COMPOUND 18)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.29 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.188 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Fragment-based and structure-guided discovery and optimization of rho kinase inhibitors.

Li, R.Martin, M.P.Liu, Y.Wang, B.Patel, R.A.Zhu, J.Y.Sun, N.Pireddu, R.Lawrence, N.J.Li, J.Haura, E.B.Sung, S.S.Guida, W.C.Schonbrunn, E.Sebti, S.M.

(2012) J Med Chem 55: 2474-2478

  • DOI: https://doi.org/10.1021/jm201289r
  • Primary Citation of Related Structures:  
    3V8S

  • PubMed Abstract: 

    Using high concentration biochemical assays and fragment-based screening assisted by structure-guided design, we discovered a novel class of Rho-kinase inhibitors. Compound 18 was equipotent for ROCK1 (IC(50) = 650 nM) and ROCK2 (IC(50) = 670 nM), whereas compound 24 was more selective for ROCK2 (IC(50) = 100 nM) over ROCK1 (IC(50) = 1690 nM). The crystal structure of the compound 18-ROCK1 complex revealed that 18 is a type 1 inhibitor that binds the hinge region in the ATP binding site. Compounds 18 and 24 inhibited potently the phosphorylation of the ROCK substrate MLC2 in intact human breast cancer cells.


  • Organizational Affiliation

    Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, USA. Rongshi.Li@moffitt.org


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Rho-associated protein kinase 1
A, B, C, D
410Homo sapiensMutation(s): 0 
Gene Names: ROCK1
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q13464 (Homo sapiens)
Explore Q13464 
Go to UniProtKB:  Q13464
PHAROS:  Q13464
GTEx:  ENSG00000067900 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ13464
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
0HD BindingDB:  3V8S IC50: 650 (nM) from 1 assay(s)
Binding MOAD:  3V8S IC50: 650 (nM) from 1 assay(s)
PDBBind:  3V8S IC50: 650 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.29 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.188 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 151.72α = 90
b = 152.11β = 90
c = 186.14γ = 90
Software Package:
Software NamePurpose
MOLREPphasing
PHENIXrefinement
HKL-2000data reduction
HKL-2000data 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: 2012-02-08
    Type: Initial release
  • Version 1.1: 2012-03-21
    Changes: Database references
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description