6C83

Structure of Aurora A (122-403) bound to inhibitory Monobody Mb2 and AMPPCP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.322 
  • R-Value Work: 0.264 
  • R-Value Observed: 0.268 

Starting Models: experimental
View more details

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.6 of the entry. See complete history


Literature

Allosteric modulation of a human protein kinase with monobodies.

Zorba, A.Nguyen, V.Koide, A.Hoemberger, M.Zheng, Y.Kutter, S.Kim, C.Koide, S.Kern, D.

(2019) Proc Natl Acad Sci U S A 116: 13937-13942

  • DOI: https://doi.org/10.1073/pnas.1906024116
  • Primary Citation of Related Structures:  
    5G15, 6C83

  • PubMed Abstract: 

    Despite being the subject of intense effort and scrutiny, kinases have proven to be consistently challenging targets in inhibitor drug design. A key obstacle has been promiscuity and consequent adverse effects of drugs targeting the ATP binding site. Here we introduce an approach to controlling kinase activity by using monobodies that bind to the highly specific regulatory allosteric pocket of the oncoprotein Aurora A (AurA) kinase, thereby offering the potential for more specific kinase modulators. Strikingly, we identify a series of highly specific monobodies acting either as strong kinase inhibitors or activators via differential recognition of structural motifs in the allosteric pocket. X-ray crystal structures comparing AurA bound to activating vs inhibiting monobodies reveal the atomistic mechanism underlying allosteric modulation. The results reveal 3 major advantages of targeting allosteric vs orthosteric sites: extreme selectivity, ability to inhibit as well as activate, and avoidance of competing with ATP that is present at high concentrations in the cells. We envision that exploiting allosteric networks for inhibition or activation will provide a general, powerful pathway toward rational drug design.


  • Organizational Affiliation

    Department of Biochemistry, Brandeis University, Waltham, MA 02454.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Aurora kinase A
A, B
285Homo 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
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Mb2 Monobody
C, D
93synthetic constructMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.322 
  • R-Value Work: 0.264 
  • R-Value Observed: 0.268 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 63.047α = 90
b = 69.916β = 90
c = 173.718γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
xia2data reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Howard Hughes Medical Institute (HHMI)United States--
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM100966
Department of Energy (DOE, United States)United StatesDE-FG02-05ER15699

Revision History  (Full details and data files)

  • Version 1.0: 2019-02-27
    Type: Initial release
  • Version 1.1: 2019-04-10
    Changes: Author supporting evidence, Data collection
  • Version 1.2: 2019-07-10
    Changes: Data collection, Database references
  • Version 1.3: 2019-07-24
    Changes: Data collection, Database references, Structure summary
  • Version 1.4: 2019-11-20
    Changes: Author supporting evidence
  • Version 1.5: 2022-03-16
    Changes: Author supporting evidence, Database references
  • Version 1.6: 2023-10-04
    Changes: Data collection, Refinement description