5VCW

CRYSTAL STRUCTURE OF HUMAN MYT1 KINASE DOMAIN IN COMPLEX WITH Pelitinib


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.25 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.196 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors.

Zhu, J.Y.Cuellar, R.A.Berndt, N.Lee, H.E.Olesen, S.H.Martin, M.P.Jensen, J.T.Georg, G.I.Schonbrunn, E.

(2017) J Med Chem 60: 7863-7875

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b00996
  • Primary Citation of Related Structures:  
    5V5Y, 5VC3, 5VC4, 5VC5, 5VC6, 5VCV, 5VCW, 5VCX, 5VCY, 5VCZ, 5VD0, 5VD1, 5VD2, 5VD3, 5VDK

  • PubMed Abstract: 

    Members of the Wee family of kinases negatively regulate the cell cycle via phosphorylation of CDK1 and are considered potential drug targets. Herein, we investigated the structure-function relationship of human Wee1, Wee2, and Myt1 (PKMYT1). Purified recombinant full-length proteins and kinase domain constructs differed substantially in phosphorylation states and catalytic competency, suggesting complex mechanisms of activation. A series of crystal structures reveal unique features that distinguish Wee1 and Wee2 from Myt1 and establish the structural basis of differential inhibition by the widely used Wee1 inhibitor MK-1775. Kinome profiling and cellular studies demonstrate that, in addition to Wee1 and Wee2, MK-1775 is an equally potent inhibitor of the polo-like kinase PLK1. Several previously unrecognized inhibitors of Wee kinases were discovered and characterized. Combined, the data provide a comprehensive view on the catalytic and structural properties of Wee kinases and a framework for the rational design of novel inhibitors thereof.


  • Organizational Affiliation

    Drug Discovery Department, Moffitt Cancer Center , Tampa, Florida 33612, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
A, B
311Homo sapiensMutation(s): 0 
Gene Names: PKMYT1MYT1
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q99640 (Homo sapiens)
Explore Q99640 
Go to UniProtKB:  Q99640
PHAROS:  Q99640
GTEx:  ENSG00000127564 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ99640
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
93J
Query on 93J

Download Ideal Coordinates CCD File 
C [auth A],
H [auth B]
(2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide
C24 H23 Cl F N5 O2
WVUNYSQLFKLYNI-AATRIKPKSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A],
I [auth B],
J [auth B],
K [auth B],
L [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
EDO
Query on EDO

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
G [auth A],
M [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
93J BindingDB:  5VCW Kd: min: 930, max: 2900 (nM) from 3 assay(s)
Binding MOAD:  5VCW Kd: 1105 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.25 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.196 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50.51α = 90
b = 112.9β = 109.27
c = 72.71γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
SERGUIdata collection
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)United StatesUO1 HD076542

Revision History  (Full details and data files)

  • Version 1.0: 2017-08-23
    Type: Initial release
  • Version 1.1: 2017-10-11
    Changes: Database references
  • Version 1.2: 2019-12-11
    Changes: Advisory, Author supporting evidence, Derived calculations
  • Version 1.3: 2023-10-04
    Changes: Data collection, Database references, Refinement description