4I80

Crystal structure of human menin in complex with a high-affinity macrocyclic peptidomimetics


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.218 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structure-Based Design of High-Affinity Macrocyclic Peptidomimetics to Block the Menin-Mixed Lineage Leukemia 1 (MLL1) Protein-Protein Interaction.

Zhou, H.Liu, L.Huang, J.Bernard, D.Karatas, H.Navarro, A.Lei, M.Wang, S.

(2013) J Med Chem 56: 1113-1123

  • DOI: https://doi.org/10.1021/jm3015298
  • Primary Citation of Related Structures:  
    4I80

  • PubMed Abstract: 

    Menin is an essential oncogenic cofactor for mixed lineage leukemia 1 (MLL1)-mediated leukemogenesis through its direct interaction with MLL1. Targeting the menin-MLL1 protein-protein interaction represents a promising strategy to block MLL1-mediated leukemogenesis. Employing a structure-based approach and starting from a linear MLL1 octapeptide, we have designed a class of potent macrocyclic peptidomimetic inhibitors of the menin-MLL1 interaction. The most potent macrocyclic peptidomimetic (MCP-1), 34, binds to menin with a K(i) value of 4.7 nM and is >600 times more potent than the corresponding acyclic peptide. Compound 34 is also less peptide-like and has a lower molecular weight than the initial MLL1 peptide. Therefore, compound 34 serves as a promising lead structure for the design of potent and cell-permeable inhibitors of the menin-MLL1 interaction.


  • Organizational Affiliation

    Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan , 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109-0934, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Menin550Homo sapiensMutation(s): 0 
Gene Names: MEN1SCG2
UniProt & NIH Common Fund Data Resources
Find proteins for O00255 (Homo sapiens)
Explore O00255 
Go to UniProtKB:  O00255
PHAROS:  O00255
GTEx:  ENSG00000133895 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO00255
Sequence Annotations
Expand
  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
macrocyclic peptidomimetic9synthetic constructMutation(s): 0 
Sequence Annotations
Expand
  • Reference Sequence
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.218 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 141.379α = 90
b = 141.379β = 90
c = 92.879γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-03-06
    Type: Initial release
  • Version 1.1: 2013-06-19
    Changes: Derived calculations
  • Version 1.2: 2017-06-21
    Changes: Database references, Source and taxonomy
  • Version 1.3: 2017-11-15
    Changes: Refinement description