3KEN

Human Eg5 in complex with S-trityl-L-cysteine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.275 
  • R-Value Work: 0.241 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Allosteric drug discrimination is coupled to mechanochemical changes in the kinesin-5 motor core.

Kim, E.D.Buckley, R.Learman, S.Richard, J.Parke, C.Worthylake, D.K.Wojcik, E.J.Walker, R.A.Kim, S.

(2010) J Biol Chem 285: 18650-18661

  • DOI: https://doi.org/10.1074/jbc.M109.092072
  • Primary Citation of Related Structures:  
    3KEN

  • PubMed Abstract: 

    Essential in mitosis, the human Kinesin-5 protein is a target for >80 classes of allosteric compounds that bind to a surface-exposed site formed by the L5 loop. Not established is why there are differing efficacies in drug inhibition. Here we compare the ligand-bound states of two L5-directed inhibitors against 15 Kinesin-5 mutants by ATPase assays and IR spectroscopy. Biochemical kinetics uncovers functional differences between individual residues at the N or C termini of the L5 loop. Infrared evaluation of solution structures and multivariate analysis of the vibrational spectra reveal that mutation and/or ligand binding not only can remodel the allosteric binding surface but also can transmit long range effects. Changes in L5-localized 3(10) helix and disordered content, regardless of substitution or drug potency, are experimentally detected. Principal component analysis couples these local structural events to two types of rearrangements in beta-sheet hydrogen bonding. These transformations in beta-sheet contacts are correlated with inhibitory drug response and are corroborated by wild type Kinesin-5 crystal structures. Despite considerable evolutionary divergence, our data directly support a theorized conserved element for long distance mechanochemical coupling in kinesin, myosin, and F(1)-ATPase. These findings also suggest that these relatively rapid IR approaches can provide structural biomarkers for clinical determination of drug sensitivity and drug efficacy in nucleotide triphosphatases.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Kinesin-like protein KIF11369Homo sapiensMutation(s): 0 
Gene Names: EG5KIF11KNSL1TRIP5
UniProt & NIH Common Fund Data Resources
Find proteins for P52732 (Homo sapiens)
Explore P52732 
Go to UniProtKB:  P52732
PHAROS:  P52732
GTEx:  ENSG00000138160 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP52732
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
ZZD BindingDB:  3KEN Ki: min: 50, max: 143.8 (nM) from 6 assay(s)
IC50: min: 140, max: 1950 (nM) from 9 assay(s)
EC50: 1720 (nM) from 1 assay(s)
PDBBind:  3KEN IC50: 4000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.275 
  • R-Value Work: 0.241 
  • Space Group: I 21 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 157.93α = 90
b = 157.93β = 90
c = 157.93γ = 90
Software Package:
Software NamePurpose
CNSrefinement
PDB_EXTRACTdata extraction
PROTEUM PLUSdata collection
SAINTdata reduction
PROTEUM PLUSdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-03-16
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description