5U1Q

Grb7-SH2 with bicyclic peptide inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Discovery, Development, and Cellular Delivery of Potent and Selective Bicyclic Peptide Inhibitors of Grb7 Cancer Target.

Watson, G.M.Kulkarni, K.Sang, J.Ma, X.Gunzburg, M.J.Perlmutter, P.Wilce, M.C.J.Wilce, J.A.

(2017) J Med Chem 60: 9349-9359

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b01320
  • Primary Citation of Related Structures:  
    5TYI, 5U06, 5U1Q

  • PubMed Abstract: 

    Grb7 is a signaling protein with critical roles in tumor cell proliferation and migration and an established cancer therapeutic target. Here we explore chemical space to develop a new bicyclic peptide inhibitor, incorporating thioether and lactam linkers that binds with affinity (K D = 1.1 μM) and specificity to the Grb7-SH2 domain. Structural analysis of the Grb7-SH2/peptide complex revealed an unexpected binding orientation underlying the binding selectivity by this new scaffold. We further incorporated carboxymethylphenylalanine and carboxyphenylalanine phosphotyrosine mimetics and arrived at an optimized inhibitor that potently binds Grb7-SH2 (K D = 0.13 μM) under physiological conditions. X-ray crystal structures of these Grb7-SH2/peptide complexes reveal the structural basis for the most potent and specific inhibitors of Grb7 developed to date. Finally, we demonstrate that cell permeable versions of these peptides successfully block Grb7 mediated interactions in a breast cancer cell line, establishing the potential of these peptides in the development of novel therapeutics targeted to Grb7.


  • Organizational Affiliation

    Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University , Wellington Road, Clayton, VIC 3800, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Growth factor receptor-bound protein 7
A, B, C, D
120Homo sapiensMutation(s): 0 
Gene Names: GRB7
UniProt & NIH Common Fund Data Resources
Find proteins for Q14451 (Homo sapiens)
Explore Q14451 
Go to UniProtKB:  Q14451
PHAROS:  Q14451
GTEx:  ENSG00000141738 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ14451
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
LYS-PHE-GLU-GLY-TYR-ASP-ASN-GLU-CSTE [auth L],
F [auth M],
G [auth N],
H [auth P]
9synthetic constructMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 122.18α = 90
b = 47.09β = 97.49
c = 94.61γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Health and Medical Research Council (NHMRC, Australia)Australia--

Revision History  (Full details and data files)

  • Version 1.0: 2017-11-15
    Type: Initial release
  • Version 1.1: 2019-01-09
    Changes: Data collection, Database references
  • Version 1.2: 2020-01-08
    Changes: Author supporting evidence, Derived calculations