6DQB

LINKED KDM5A JMJ DOMAIN FORMING COVALENT BOND TO INHIBITOR N71 i.e. 2-((3-(4-(dimethylamino)but-2-enamido)phenyl)(2-(piperidin-1-yl)ethoxy)methyl)thieno[3,2-b]pyridine-7-carboxylic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.79 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.171 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A.

Horton, J.R.Woodcock, C.B.Chen, Q.Liu, X.Zhang, X.Shanks, J.Rai, G.Mott, B.T.Jansen, D.J.Kales, S.C.Henderson, M.J.Cyr, M.Pohida, K.Hu, X.Shah, P.Xu, X.Jadhav, A.Maloney, D.J.Hall, M.D.Simeonov, A.Fu, H.Vertino, P.M.Cheng, X.

(2018) J Med Chem 61: 10588-10601

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b01219
  • Primary Citation of Related Structures:  
    6DQ4, 6DQ5, 6DQ6, 6DQ8, 6DQ9, 6DQA, 6DQB

  • PubMed Abstract: 

    The active sites of hundreds of human α-ketoglutarate (αKG) and Fe(II)-dependent dioxygenases are exceedingly well preserved, which challenges the design of selective inhibitors. We identified a noncatalytic cysteine (Cys481 in KDM5A) near the active sites of KDM5 histone H3 lysine 4 demethylases, which is absent in other histone demethylase families, that could be explored for interaction with the cysteine-reactive electrophile acrylamide. We synthesized analogs of a thienopyridine-based inhibitor chemotype, namely, 2-((3-aminophenyl)(2-(piperidin-1-yl)ethoxy)methyl)thieno[3,2- b]pyridine-7-carboxylic acid (N70) and a derivative containing a (dimethylamino)but-2-enamido)phenyl moiety (N71) designed to form a covalent interaction with Cys481. We characterized the inhibitory and binding activities against KDM5A and determined the cocrystal structures of the catalytic domain of KDM5A in complex with N70 and N71. Whereas the noncovalent inhibitor N70 displayed αKG-competitive inhibition that could be reversed after dialysis, inhibition by N71 was dependent on enzyme concentration and persisted even after dialysis, consistent with covalent modification.


  • Organizational Affiliation

    Department of Molecular and Cellular Oncology , The University of Texas MD Anderson Cancer Center , Houston , Texas 77030 , United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Linked KDM5A Jmj Domain330Homo sapiensMutation(s): 0 
Gene Names: KDM5AJARID1ARBBP2RBP2
EC: 1.14.11
UniProt & NIH Common Fund Data Resources
Find proteins for P29375 (Homo sapiens)
Explore P29375 
Go to UniProtKB:  P29375
PHAROS:  P29375
GTEx:  ENSG00000073614 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP29375
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HZM
Query on HZM

Download Ideal Coordinates CCD File 
D [auth A]2-{(S)-(3-{[4-(dimethylamino)butanoyl]amino}phenyl)[2-(piperidin-1-yl)ethoxy]methyl}thieno[3,2-b]pyridine-7-carboxylic acid
C28 H36 N4 O4 S
GTUZDQNWYGEDTB-SANMLTNESA-N
HZV
Query on HZV

Download Ideal Coordinates CCD File 
C [auth A]2-{(R)-(3-{[4-(dimethylamino)butanoyl]amino}phenyl)[2-(piperidin-1-yl)ethoxy]methyl}thieno[3,2-b]pyridine-7-carboxylic acid
C28 H36 N4 O4 S
GTUZDQNWYGEDTB-AREMUKBSSA-N
H77
Query on H77

Download Ideal Coordinates CCD File 
B [auth A]2-{(R)-(3-{[(2E)-4-(dimethylamino)but-2-enoyl]amino}phenyl)[2-(piperidin-1-yl)ethoxy]methyl}thieno[3,2-b]pyridine-7-carboxylic acid
C28 H34 N4 O4 S
KIIDGZQVWULCMZ-GYAHLDOBSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
H [auth A],
I [auth A]
DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
MN
Query on MN

Download Ideal Coordinates CCD File 
E [auth A]MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.79 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.171 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 117.007α = 90
b = 62.325β = 92.24
c = 46.751γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM049245-23

Revision History  (Full details and data files)

  • Version 1.0: 2018-11-21
    Type: Initial release
  • Version 1.1: 2019-05-01
    Changes: Data collection, Database references
  • Version 1.2: 2020-01-01
    Changes: Author supporting evidence
  • Version 1.3: 2023-10-11
    Changes: Data collection, Database references, Derived calculations, Refinement description