3O0G

Crystal Structure of Cdk5:p25 in complex with an ATP analogue


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.228 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Defining Cdk5 ligand chemical space with small molecule inhibitors of Tau phosphorylation

Ahn, J.S.Radhakrishnan, M.L.Mapelli, M.Choi, S.Tidor, B.Cuny, G.D.Musacchio, A.Yeh, L.Kosik, S.K.

(2005) Chem Biol 12: 811-823

  • DOI: https://doi.org/10.1016/j.chembiol.2005.05.011
  • Primary Citation of Related Structures:  
    3O0G

  • PubMed Abstract: 

    Cyclin-dependent kinase 5 (Cdk5) is widely viewed as a possible target for a wide variety of neurological disorders. One pathological role attributed to Cdk5 is the abnormal phosphorylation of tau that may lead to the neuronal inclusions known as neurofibrillary tangles. A high through-put screen for inhibitors of Cdk5-mediated phosphorylation of tau resulted in three compounds with distinct mechanisms of action. One compound is competitive with ATP and has a high affinity for the Cdk5 ATP binding pocket. The second compound also competes with ATP, is noncompetitive with tau, and (uniquely among this class of inhibitors) displaces adjacent amino acid residues to make room for the nitrophenyl group. A third compound did not compete with ATP, but did compete with tau at low concentrations of tau. The SAR and charge optimization derived from cocrystals of the two ATP competitors along with cocrystals of three other ATP competitors map out the importance of filling and properly charging different regions of the ATP binding pocket. Taken together, this analysis shows how the structure of Cdk5 constrains the space of potential inhibitors and reveals a pocket unfilled in all of the structures. These leads could be a starting point for structure-based drug design of more potent and selective inhibitors.


  • Organizational Affiliation

    Department of Neurology and Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cell division protein kinase 5A,
C [auth B]
292Homo sapiensMutation(s): 1 
Gene Names: Cdk5
EC: 2.7.11.22
UniProt & NIH Common Fund Data Resources
Find proteins for Q00535 (Homo sapiens)
Explore Q00535 
Go to UniProtKB:  Q00535
PHAROS:  Q00535
GTEx:  ENSG00000164885 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ00535
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Cyclin-dependent kinase 5 activator 1B [auth D],
D [auth E]
149Homo sapiensMutation(s): 0 
Gene Names: p25
UniProt & NIH Common Fund Data Resources
Find proteins for Q15078 (Homo sapiens)
Explore Q15078 
Go to UniProtKB:  Q15078
PHAROS:  Q15078
GTEx:  ENSG00000176749 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ15078
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3O0
Query on 3O0

Download Ideal Coordinates CCD File 
E [auth B]{4-amino-2-[(4-chlorophenyl)amino]-1,3-thiazol-5-yl}(3-nitrophenyl)methanone
C16 H11 Cl N4 O3 S
YQRVBHMYUSGXHL-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3O0 PDBBind:  3O0G Ki: 600 (nM) from 1 assay(s)
Binding MOAD:  3O0G Ki: 600 (nM) from 1 assay(s)
BindingDB:  3O0G IC50: min: 750, max: 2000 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.228 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 117.124α = 90
b = 117.124β = 90
c = 155.599γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
AMoREphasing
CNSrefinement
PDB_EXTRACTdata extraction
DENZOdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2011-01-26 
  • Deposition Author(s): Mapelli, M.

Revision History  (Full details and data files)

  • Version 1.0: 2011-01-26
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2019-07-17
    Changes: Data collection, Refinement description
  • Version 1.3: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description