7ZKR

Human GABARAP in complex with stapled peptide Pen3-ortho


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.10 Å
  • R-Value Free: 0.167 
  • R-Value Work: 0.140 
  • R-Value Observed: 0.141 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Structure-Based Design of Stapled Peptides That Bind GABARAP and Inhibit Autophagy.

Brown, H.Chung, M.Uffing, A.Batistatou, N.Tsang, T.Doskocil, S.Mao, W.Willbold, D.Bast Jr., R.C.Lu, Z.Weiergraber, O.H.Kritzer, J.A.

(2022) J Am Chem Soc 144: 14687-14697

  • DOI: https://doi.org/10.1021/jacs.2c04699
  • Primary Citation of Related Structures:  
    7ZKR, 7ZL7

  • PubMed Abstract: 

    The LC3/GABARAP family of proteins is involved in nearly every stage of autophagy. Inhibition of LC3/GABARAP proteins is a promising approach to blocking autophagy, which sensitizes advanced cancers to DNA-damaging chemotherapy. Here, we report the structure-based design of stapled peptides that inhibit GABARAP with nanomolar affinities. Small changes in staple structure produced stapled peptides with very different binding modes and functional differences in LC3/GABARAP paralog selectivity, ranging from highly GABARAP-specific to broad inhibition of both subfamilies. The stapled peptides exhibited considerable cytosolic penetration and resistance to biological degradation. They also reduced autophagic flux in cultured ovarian cancer cells and sensitized ovarian cancer cells to cisplatin. These small, potent stapled peptides represent promising autophagy-modulating compounds that can be developed as novel cancer therapeutics and novel mediators of targeted protein degradation.


  • Organizational Affiliation

    Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Gamma-aminobutyric acid receptor-associated protein119Homo sapiensMutation(s): 0 
Gene Names: GABARAPFLC3BHT004
UniProt & NIH Common Fund Data Resources
Find proteins for O95166 (Homo sapiens)
Explore O95166 
Go to UniProtKB:  O95166
PHAROS:  O95166
GTEx:  ENSG00000170296 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO95166
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Pen3-ortho14synthetic 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: 1.10 Å
  • R-Value Free: 0.167 
  • R-Value Work: 0.140 
  • R-Value Observed: 0.141 
  • Space Group: I 2 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 99.03α = 90
b = 99.03β = 90
c = 99.03γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
MOLREPphasing

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM125856
National Science Foundation (NSF, United States)United StatesUS, 2003010
German Research Foundation (DFG)Germany267205415

Revision History  (Full details and data files)

  • Version 1.0: 2022-08-31
    Type: Initial release
  • Version 1.1: 2024-01-31
    Changes: Data collection, Refinement description