7NUS

X-RAY STRUCTURE OF HDM2/CMR19 AT 1.45A: Discovery, X-ray structure and CPP-conjugation enabled uptake of p53/MDM2 macrocyclic peptide inhibitors

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.197 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.178 

Starting Model: experimental
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This is version 1.3 of the entry. See complete history. 


Literature

Discovery, X-ray structure and CPP-conjugation enabled uptake of p53/MDM2 macrocyclic peptide inhibitors.

Schneider, A.F.L., Kallen, J., Ottl, J., Reid, P.C., Ripoche, S., Ruetz, S., Stachyra, T.M., Hintermann, S., Dumelin, C.E., Hackenberger, C.P.R., Marzinzik, A.L.

(2021) RSC Chem Biol 2: 1661-1668

  • DOI: https://doi.org/10.1039/d1cb00056j
  • Primary Citation of Related Structures:  
    7NUS

  • PubMed Abstract: 

    Mouse double minute 2 homolog (MDM2, Hdm2) is an important negative regulator of the tumor suppressor p53. Using a mRNA based display technique to screen a library of >10 12 in vitro -translated cyclic peptides, we have identified a macrocyclic ligand that shows picomolar potency on MDM2. X-Ray crystallography reveals a novel binding mode utilizing a unique pharmacophore to occupy the Phe/Trp/Leu pockets on MDM2. Conjugation of a cyclic cell-penetrating peptide (cCPP) to the initially non cell-permeable ligand enables cellular uptake and a pharmacodynamic response in SJSA-1 cells. The demonstrated enhanced intracellular availability of cyclic peptides that are identified by a display technology exemplifies a process for the application of intracellular tools for drug discovery projects.

    • Organizational Affiliation: 

    Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10 Berlin 13125 Germany [email protected].


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
E3 ubiquitin-protein ligase Mdm2
A, B, C
96Homo sapiensMutation(s): 0 
Gene Names: MDM2
EC: 2.3.2.27
UniProt & NIH Common Fund Data Resources
Find proteins for Q00987 (Homo sapiens)
Explore Q00987 
Go to UniProtKB:  Q00987
PHAROS:  Q00987
GTEx:  ENSG00000135679 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ00987
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
p53/MDM2 macrocyclic peptide inhibitor
D, E, F
15synthetic 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: 1.45 Å
  • R-Value Free: 0.197 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.178 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 140.78α = 90
b = 40.306β = 112.2
c = 70.198γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction

Structure Validation

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Entry History 

Deposition Data

  • Released Date: 2021-09-22 
    • Deposition Author(s): Kallen, J.

Revision History  (Full details and data files)

  • Version 1.0: 2021-09-22
    Type: Initial release
  • Version 1.1: 2021-09-29
    Changes: Derived calculations
  • Version 1.2: 2022-02-02
    Changes: Database references
  • Version 1.3: 2024-01-31
    Changes: Data collection, Refinement description