2X2R

Crystal structure of human kinesin Eg5 in complex with (R)-2-amino-3-((4-chlorophenyl)diphenylmethylthio)propanoic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.175 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure-Activity Relationship and Multidrug Resistance Study of New S-Trityl-L-Cysteine Derivatives as Inhibitors of Eg5.

Kaan, H.Y.K.Weiss, J.Menger, D.Ulaganathan, V.Tkocz, K.Laggner, C.Popowycz, F.Joseph, B.Kozielski, F.

(2011) J Med Chem 54: 1576

  • DOI: https://doi.org/10.1021/jm100991m
  • Primary Citation of Related Structures:  
    2X2R, 2XAE

  • PubMed Abstract: 

    The mitotic spindle is a validated target for cancer chemotherapy. Drugs such as taxanes and vinca alkaloids specifically target microtubules and cause the mitotic spindle to collapse. However, toxicity and resistance are problems associated with these drugs. Thus, alternative approaches to inhibiting the mitotic spindle are being pursued. These include targeting Eg5, a human kinesin involved in the formation of the bipolar spindle. We previously identified S-trityl-L-cysteine (STLC) as a potent allosteric inhibitor of Eg5. Here, we report the synthesis of a new series of STLC-like compounds with in vitro inhibition in the low nanomolar range. We also performed a multidrug resistance study in cell lines overexpressing P-glycoprotein and showed that some of these inhibitors may have the potential to overcome susceptibility to this efflux pump. Finally, we performed molecular docking of the compounds and determined the structures of two Eg5-inhibitor complexes to explain the structure-activity relationship of these compounds.


  • Organizational Affiliation

    The Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, Scotland, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
KINESIN-LIKE PROTEIN KIF11
A, B, C
368Homo sapiensMutation(s): 0 
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
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ADP
Query on ADP

Download Ideal Coordinates CCD File 
D [auth A],
G [auth B],
J [auth C]
ADENOSINE-5'-DIPHOSPHATE
C10 H15 N5 O10 P2
XTWYTFMLZFPYCI-KQYNXXCUSA-N
X2O
Query on X2O

Download Ideal Coordinates CCD File 
E [auth A],
H [auth B],
K [auth C]
(2R)-2-AMINO-3-[(2R)-2-METHYL-1,1-DIPHENYL-BUTYL]SULFANYL-PROPANOIC ACID
C20 H25 N O2 S
AEXWHNCQYTYTMP-QAPCUYQASA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
F [auth A],
I [auth B],
L [auth C]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
X2O Binding MOAD:  2X2R Ki: 76.2 (nM) from 1 assay(s)
PDBBind:  2X2R Ki: 76.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.175 
  • Space Group: P 32
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 96.35α = 90
b = 96.35β = 90
c = 124.4γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
iMOSFLMdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-01-26
    Type: Initial release
  • Version 1.1: 2011-05-19
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description