4CQG

The crystal structure of MPK38 in complex with OTSSP167, an orally- administrative MELK selective inhibitor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.57 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.207 

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Literature

The crystal structure of MPK38 in complex with OTSSP167, an orally administrative MELK selective inhibitor.

Cho, Y.S., Kang, Y., Kim, K., Cha, Y.J., Cho, H.S.

(2014) Biochem Biophys Res Commun 447: 7-11

  • DOI: https://doi.org/10.1016/j.bbrc.2014.03.034
  • Primary Citation of Related Structures:  
    4CQG

  • PubMed Abstract: 

    Murine protein serine/threonine kinase 38 (MPK38), also known as maternal embryonic leucine zipper kinase (MELK), has been associated with various human cancers and plays an important role in the formation of cancer stem cells. OTSSP167, a MELK selective inhibitor, exhibits a strong in vitro activity, conferring an IC50 of 0.41nM and in vivo effect on various human cancer xenograft models. Here, we report the crystal structure of MPK38 (T167E), an active mutant, in complex with OTSSP167 and describe its detailed protein-inhibitor interactions. Comparison with the previous determined structure of MELK bound to the nanomolar inhibitors shows that OTSSP167 effectively fits into the active site, thus offering an opportunity for structure-based development and optimization of MELK inhibitors.

    • Organizational Affiliation: 

    Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Maternal embryonic leucine zipper kinase331Mus musculusMutation(s): 1 
Gene Names: Melk, Kiaa0175, Pk38
EC: 2.7.11.1 (PDB Primary Data), 2.7.10.2 (PDB Primary Data)
UniProt
Find proteins for Q61846 (Mus musculus)
Explore Q61846 
Go to UniProtKB:  Q61846
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ61846
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
OT5
Query on OT5
Download Ideal Coordinates CCD File 
B [auth A]1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-({trans-4-[(dimethylamino)methyl]cyclohexyl}amino)-1,5-naphthyridin-3-yl]ethanone
C25 H28 Cl2 N4 O2
DKZYXHCYPUVGAF-JCNLHEQBSA-N
SO4
Query on SO4
Download Ideal Coordinates CCD File 
C [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
OT5 BindingDB:  4CQG Kd: 15 (nM) from 1 assay(s)
IC50: min: 0.4, max: 1.1 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.57 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.207 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 35.96α = 90
b = 75.76β = 90
c = 128.12γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
MOSFLMdata scaling
MOLREPphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-07-09
    Type: Initial release
  • Version 1.1: 2019-04-24
    Changes: Data collection, Database references, Experimental preparation, Other, Source and taxonomy, Structure summary
  • Version 1.2: 2019-07-17
    Changes: Data collection
  • Version 1.3: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description