3MFR

CASK-4M CaM Kinase Domain, native


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Evolution of CASK into a Mg2+-sensitive kinase.

Mukherjee, K.Sharma, M.Jahn, R.Wahl, M.C.Sudhof, T.C.

(2010) Sci Signal 3: ra33-ra33

  • DOI: https://doi.org/10.1126/scisignal.2000800
  • Primary Citation of Related Structures:  
    3MFR, 3MFS, 3MFT, 3MFU

  • PubMed Abstract: 

    All known protein kinases, except CASK [calcium/calmodulin (CaM)-activated serine-threonine kinase], require magnesium ions (Mg(2+)) to stimulate the transfer of a phosphate from adenosine 5'-triphosphate (ATP) to a protein substrate. The CaMK (calcium/calmodulin-dependent kinase) domain of CASK shows activity in the absence of Mg(2+); indeed, it is inhibited by divalent ions including Mg(2+). Here, we converted the Mg(2+)-inhibited wild-type CASK kinase (CASK(WT)) into a Mg(2+)-stimulated kinase (CASK(4M)) by substituting four residues within the ATP-binding pocket. Crystal structures of CASK(4M) with and without bound nucleotide and Mn(2+), together with kinetic analyses, demonstrated that Mg(2+) accelerates catalysis of CASK(4M) by stabilizing the transition state, enhancing the leaving group properties of adenosine 5'-diphosphate, and indirectly shifting the position of the gamma-phosphate of ATP. Phylogenetic analysis revealed that the four residues conferring Mg(2+)-mediated stimulation were substituted from CASK during early animal evolution, converting a primordial, Mg(2+)-coordinating form of CASK into a Mg(2+)-inhibited kinase. This emergence of Mg(2+) sensitivity (inhibition by Mg(2+)) conferred regulation of CASK activity by divalent cations, in parallel with the evolution of the animal nervous systems.


  • Organizational Affiliation

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 1050 Arastradero Road, Palo Alto, CA 94304, USA. konark@brandeis.edu


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Peripheral plasma membrane protein CASK351Homo sapiensMutation(s): 4 
Gene Names: CASKLIN2
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for O14936 (Homo sapiens)
Explore O14936 
Go to UniProtKB:  O14936
PHAROS:  O14936
GTEx:  ENSG00000147044 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO14936
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ANP
Query on ANP

Download Ideal Coordinates CCD File 
B [auth A]PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER
C10 H17 N6 O12 P3
PVKSNHVPLWYQGJ-KQYNXXCUSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.7α = 90
b = 61.837β = 90
c = 100.164γ = 90
Software Package:
Software NamePurpose
MAR345dtbdata collection
MOLREPphasing
REFMACrefinement
DENZOdata reduction
SCALEPACKdata 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: 2010-04-28
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2021-10-06
    Changes: Database references, Derived calculations
  • Version 1.3: 2023-09-06
    Changes: Data collection, Refinement description