5A3W

Crystal structure of human PLU-1 (JARID1B) in complex with Pyridine-2, 6-dicarboxylic Acid (PDCA)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.186 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Structural Analysis of Human Kdm5B Guides Histone Demethylase Inhibitor Development.

Johansson, C.Velupillai, S.Tumber, A.Szykowska, A.Hookway, E.S.Nowak, R.P.Strain-Damerell, C.Gileadi, C.Philpott, M.Burgess-Brown, N.Wu, N.Kopec, J.Nuzzi, A.Steuber, H.Egner, U.Badock, V.Munro, S.Lathangue, N.B.Westaway, S.Brown, J.Athanasou, N.Prinjha, R.Brennan, P.E.Oppermann, U.

(2016) Nat Chem Biol 12: 539

  • DOI: https://doi.org/10.1038/nchembio.2087
  • Primary Citation of Related Structures:  
    4UF0, 5A1F, 5A3P, 5A3T, 5A3W, 5FPU, 5FPV, 5FUN, 5FUP, 5FV3, 5FWJ

  • PubMed Abstract: 

    Members of the KDM5 (also known as JARID1) family are 2-oxoglutarate- and Fe(2+)-dependent oxygenases that act as histone H3K4 demethylases, thereby regulating cell proliferation and stem cell self-renewal and differentiation. Here we report crystal structures of the catalytic core of the human KDM5B enzyme in complex with three inhibitor chemotypes. These scaffolds exploit several aspects of the KDM5 active site, and their selectivity profiles reflect their hybrid features with respect to the KDM4 and KDM6 families. Whereas GSK-J1, a previously identified KDM6 inhibitor, showed about sevenfold less inhibitory activity toward KDM5B than toward KDM6 proteins, KDM5-C49 displayed 25-100-fold selectivity between KDM5B and KDM6B. The cell-permeable derivative KDM5-C70 had an antiproliferative effect in myeloma cells, leading to genome-wide elevation of H3K4me3 levels. The selective inhibitor GSK467 exploited unique binding modes, but it lacked cellular potency in the myeloma system. Taken together, these structural leads deliver multiple starting points for further rational and selective inhibitor design.


  • Organizational Affiliation

    Structural Genomics Consortium, University of Oxford, Headington, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
LYSINE-SPECIFIC DEMETHYLASE 5B481Homo sapiensMutation(s): 0 
EC: 1.14.11
UniProt & NIH Common Fund Data Resources
Find proteins for Q9UGL1 (Homo sapiens)
Explore Q9UGL1 
Go to UniProtKB:  Q9UGL1
PHAROS:  Q9UGL1
GTEx:  ENSG00000117139 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9UGL1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
EPE
Query on EPE

Download Ideal Coordinates CCD File 
H [auth A]4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID
C8 H18 N2 O4 S
JKMHFZQWWAIEOD-UHFFFAOYSA-N
PD2
Query on PD2

Download Ideal Coordinates CCD File 
E [auth A]PYRIDINE-2,4-DICARBOXYLIC ACID
C7 H5 N O4
MJIVRKPEXXHNJT-UHFFFAOYSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
G [auth A]PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
I [auth A],
J [auth A],
K [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
MN
Query on MN

Download Ideal Coordinates CCD File 
F [auth A]MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
D [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
PD2 Binding MOAD:  5A3W Ki: 390 (nM) from 1 assay(s)
BindingDB:  5A3W IC50: min: 1500, max: 3000 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.186 
  • Space Group: P 65 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 142.102α = 90
b = 142.102β = 90
c = 152.256γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
SCALAdata scaling
CCP4-AUTOMRphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2015-06-17
    Type: Initial release
  • Version 1.1: 2016-05-25
    Changes: Database references
  • Version 1.2: 2016-06-01
    Changes: Database references
  • Version 1.3: 2016-06-29
    Changes: Database references
  • Version 1.4: 2018-01-24
    Changes: Structure summary