4QMW

MST3 IN COMPLEX WITH PP-121, 1-CYCLOPENTYL-3-(1H-PYRROLO[2,3-B]PYRIDIN-5-YL)-1H-PYRAZOLO[3,4-D]PYRIMIDIN-4-AMINE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.176 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of Diverse Small-Molecule Inhibitors of Mammalian Sterile20-like Kinase 3 (MST3).

Olesen, S.H.Zhu, J.Y.Martin, M.P.Schonbrunn, E.

(2016) ChemMedChem 11: 1137-1144

  • DOI: https://doi.org/10.1002/cmdc.201600115
  • Primary Citation of Related Structures:  
    4QML, 4QMM, 4QMN, 4QMO, 4QMP, 4QMQ, 4QMS, 4QMT, 4QMU, 4QMV, 4QMW, 4QMX, 4QMY, 4QMZ, 4QNA, 4QO9

  • PubMed Abstract: 

    Increasing evidence suggests key roles for members of the mammalian Sterile20-like (MST) family of kinases in many aspects of biology. MST3 is a member of the STRIPAK complex, the deregulation of which has recently been associated with cancer cell migration and metastasis. Targeting MST3 with small-molecule inhibitors may be beneficial for the treatment of certain cancers, but little information exists on the potential of kinase inhibitor scaffolds to engage with MST3. In this study we screened MST3 against a library of 277 kinase inhibitors using differential scanning fluorimetry and confirmed 14 previously unknown MST3 inhibitors by X-ray crystallography. These compounds, of which eight are in clinical trials or FDA approved, comprise nine distinct chemical scaffolds that inhibit MST3 enzymatic activity with IC50 values between 0.003 and 23 μm. The structure-activity relationships explain the differential inhibitory activity of these compounds against MST3 and the structural basis for high binding potential, the information of which may serve as a framework for the rational design of MST3-selective inhibitors as potential therapeutics and to interrogate the function of this enzyme in diseased cells.


  • Organizational Affiliation

    Drug Discovery Department, Moffitt Cancer Center, Tampa, FL, 33612, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
SERINE/THREONINE-PROTEIN KINASE 24310Homo sapiensMutation(s): 0 
Gene Names: STK24MST3STK3
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y6E0 (Homo sapiens)
Explore Q9Y6E0 
Go to UniProtKB:  Q9Y6E0
PHAROS:  Q9Y6E0
GTEx:  ENSG00000102572 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9Y6E0
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
KS1
Query on KS1

Download Ideal Coordinates CCD File 
B [auth A]1-cyclopentyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
C17 H17 N7
NVRXTLZYXZNATH-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
D [auth A]ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
TPO
Query on TPO
A
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Binding Affinity Annotations 
IDSourceBinding Affinity
KS1 Binding MOAD:  4QMW IC50: 86 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.176 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 47.763α = 90
b = 55.337β = 111.01
c = 60.233γ = 90
Software Package:
Software NamePurpose
SERGUIdata collection
PHENIXmodel building
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-07-01
    Type: Initial release
  • Version 1.1: 2016-06-15
    Changes: Database references
  • Version 1.2: 2016-07-13
    Changes: Database references
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description