6HJJ

Crystal structure of Aurora-A L210C catalytic domain in complex with ASDO6 ligand


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.13 Å
  • R-Value Free: 0.269 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.212 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Type II Kinase Inhibitors Targeting Cys-Gatekeeper Kinases Display Orthogonality with Wild Type and Ala/Gly-Gatekeeper Kinases.

Ocasio, C.A.Warkentin, A.A.McIntyre, P.J.Barkovich, K.J.Vesely, C.Spencer, J.Shokat, K.M.Bayliss, R.

(2018) ACS Chem Biol 13: 2956-2965

  • DOI: https://doi.org/10.1021/acschembio.8b00592
  • Primary Citation of Related Structures:  
    6HJJ, 6HJK

  • PubMed Abstract: 

    Analogue-sensitive (AS) kinases contain large to small mutations in the gatekeeper position rendering them susceptible to inhibition with bulky analogues of pyrazolopyrimidine-based Src kinase inhibitors (e.g., PP1). This "bump-hole" method has been utilized for at least 85 of ∼520 kinases, but many kinases are intolerant to this approach. To expand the scope of AS kinase technology, we designed type II kinase inhibitors, ASDO2/6 (analogue-sensitive "DFG-out" kinase inhibitors 2 and 6), that target the "DFG-out" conformation of Cys-gatekeeper kinases with submicromolar potency. We validated this system in vitro against Greatwall kinase (GWL), Aurora-A kinase, and cyclin-dependent kinase-1 and in cells using M110C-GWL-expressing mouse embryonic fibroblasts. These Cys-gatekeeper kinases were sensitive to ASDO2/6 inhibition but not AS kinase inhibitor 3MB-PP1 and vice versa. These compounds, with AS kinase inhibitors, have the potential to inhibit multiple AS kinases independently with applications in systems level and translational kinase research as well as the rational design of type II kinase inhibitors targeting endogenous kinases.


  • Organizational Affiliation

    Genome Damage and Stability Centre, School of Life Sciences , University of Sussex , Falmer, Brighton BN1 9RQ , U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Aurora kinase A285Homo sapiensMutation(s): 3 
Gene Names: AURKAAIKAIRK1ARK1AURAAYK1BTAKIAK1STK15STK6
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for O14965 (Homo sapiens)
Explore O14965 
Go to UniProtKB:  O14965
PHAROS:  O14965
GTEx:  ENSG00000087586 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO14965
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
G7T (Subject of Investigation/LOI)
Query on G7T

Download Ideal Coordinates CCD File 
B [auth A]~{N}-[4-(4-azanyl-1-propan-2-yl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-methyl-phenyl]-4-[4-fluoranyl-3-(trifluoromethyl)phenyl]-4-oxidanylidene-butanamide
C26 H24 F4 N6 O2
QTIJDEKGLBXUPB-UHFFFAOYSA-N
PGF
Query on PGF

Download Ideal Coordinates CCD File 
I [auth A]2,5,8,11-TETRAOXATRIDECANE
C9 H20 O4
JRRDISHSXWGFRF-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A],
H [auth A]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
CL
Query on CL

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
E [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
G7T Binding MOAD:  6HJJ IC50: 1700 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.13 Å
  • R-Value Free: 0.269 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.212 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 82.027α = 90
b = 82.027β = 90
c = 172.609γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Cancer Research UKUnited KingdomC24461/A23302
Medical Research Council (United Kingdom)United KingdomMR/K016903

Revision History  (Full details and data files)

  • Version 1.0: 2018-10-03
    Type: Initial release
  • Version 1.1: 2018-10-31
    Changes: Data collection, Database references