5L3G

LSD1-CoREST1 in complex with polymyxin E (colistin)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.197 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.173 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Polymyxins and quinazolines are LSD1/KDM1A inhibitors with unusual structural features.

Speranzini, V.Rotili, D.Ciossani, G.Pilotto, S.Marrocco, B.Forgione, M.Lucidi, A.Forneris, F.Mehdipour, P.Velankar, S.Mai, A.Mattevi, A.

(2016) Sci Adv 2: e1601017-e1601017

  • DOI: https://doi.org/10.1126/sciadv.1601017
  • Primary Citation of Related Structures:  
    5L3E, 5L3F, 5L3G, 5LBQ

  • PubMed Abstract: 

    Because of its involvement in the progression of several malignant tumors, the histone lysine-specific demethylase 1 (LSD1) has become a prominent drug target in modern medicinal chemistry research. We report on the discovery of two classes of noncovalent inhibitors displaying unique structural features. The antibiotics polymyxins bind at the entrance of the substrate cleft, where their highly charged cyclic moiety interacts with a cluster of positively charged amino acids. The same site is occupied by quinazoline-based compounds, which were found to inhibit the enzyme through a most peculiar mode because they form a pile of five to seven molecules that obstruct access to the active center. These data significantly indicate unpredictable strategies for the development of epigenetic inhibitors.


  • Organizational Affiliation

    Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Lysine-specific histone demethylase 1A730Homo sapiensMutation(s): 0 
Gene Names: KDM1AAOF2KDM1KIAA0601LSD1
EC: 1
UniProt & NIH Common Fund Data Resources
Find proteins for O60341 (Homo sapiens)
Explore O60341 
Go to UniProtKB:  O60341
PHAROS:  O60341
GTEx:  ENSG00000004487 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO60341
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
REST corepressor 1178Homo sapiensMutation(s): 0 
Gene Names: RCOR1KIAA0071RCOR
UniProt & NIH Common Fund Data Resources
Find proteins for Q9UKL0 (Homo sapiens)
Explore Q9UKL0 
Go to UniProtKB:  Q9UKL0
PHAROS:  Q9UKL0
GTEx:  ENSG00000089902 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9UKL0
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
polymyxin E11Paenibacillus polymyxaMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
DAB
Query on DAB
C
L-PEPTIDE LINKINGC4 H10 N2 O2ALA
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.197 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.173 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 119.864α = 90
b = 179.49β = 90
c = 236.985γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
AIRCItalyIG-15208
MIURItalyProgetto Bandiera Epigenomica - EPIGEN
ItalyRF-2010-2318330
ItalySapienza Award Project 2014
ItalyIIT-Sapienza Project
AIRC-Fondazione CariploItalyTRIDEO Id. 17515
MIURItalyPRIN 2012CTAYSY
EUFP7 Projects BLUEPRINT/282510
A-PARADDISE/602080
Giovanni Armenise-Harvard foundationUnited StatesCareer development award 2013
MIURItalyProgramma Giovani Ricercatori Rita Levi-Montalcini 2013

Revision History  (Full details and data files)

  • Version 1.0: 2016-09-21
    Type: Initial release
  • Version 1.1: 2016-10-05
    Changes: Database references
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description