5DN3

Aurora A in complex with ATP and AA35.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.192 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2.

Janecek, M.Rossmann, M.Sharma, P.Emery, A.Huggins, D.J.Stockwell, S.R.Stokes, J.E.Tan, Y.S.Almeida, E.G.Hardwick, B.Narvaez, A.J.Hyvonen, M.Spring, D.R.McKenzie, G.J.Venkitaraman, A.R.

(2016) Sci Rep 6: 28528-28528

  • DOI: https://doi.org/10.1038/srep28528
  • Primary Citation of Related Structures:  
    5DN3, 5DNR, 5DOS, 5DPV, 5DR2, 5DR6, 5DR9, 5DRD, 5DT0, 5DT3, 5DT4

  • PubMed Abstract: 

    The essential mitotic kinase Aurora A (AURKA) is controlled during cell cycle progression via two distinct mechanisms. Following activation loop autophosphorylation early in mitosis when it localizes to centrosomes, AURKA is allosterically activated on the mitotic spindle via binding to the microtubule-associated protein, TPX2. Here, we report the discovery of AurkinA, a novel chemical inhibitor of the AURKA-TPX2 interaction, which acts via an unexpected structural mechanism to inhibit AURKA activity and mitotic localization. In crystal structures, AurkinA binds to a hydrophobic pocket (the 'Y pocket') that normally accommodates a conserved Tyr-Ser-Tyr motif from TPX2, blocking the AURKA-TPX2 interaction. AurkinA binding to the Y- pocket induces structural changes in AURKA that inhibit catalytic activity in vitro and in cells, without affecting ATP binding to the active site, defining a novel mechanism of allosteric inhibition. Consistent with this mechanism, cells exposed to AurkinA mislocalise AURKA from mitotic spindle microtubules. Thus, our findings provide fresh insight into the catalytic mechanism of AURKA, and identify a key structural feature as the target for a new class of dual-mode AURKA inhibitors, with implications for the chemical biology and selective therapeutic targeting of structurally related kinases.


  • Organizational Affiliation

    MRC Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Aurora kinase A272Homo sapiensMutation(s): 0 
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
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
TPO
Query on TPO
A
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Binding Affinity Annotations 
IDSourceBinding Affinity
5DN Binding MOAD:  5DN3 Kd: 3770 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.192 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 81.65α = 90
b = 81.65β = 90
c = 136.91γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata scaling
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Wellcome TrustUnited Kingdom090340/Z/09/Z

Revision History  (Full details and data files)

  • Version 1.0: 2016-07-20
    Type: Initial release
  • Version 2.0: 2017-08-30
    Changes: Atomic model, Author supporting evidence
  • Version 2.1: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description