6WBW

Structure of Human HDAC2 in complex with an ethyl ketone inhibitor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.46 Å
  • R-Value Free: 0.197 
  • R-Value Work: 0.172 
  • 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

Discovery of ethyl ketone-based HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation.

Yu, W., Liu, J., Yu, Y., Zhang, V., Clausen, D., Kelly, J., Wolkenberg, S., Beshore, D., Duffy, J.L., Chung, C.C., Myers, R.W., Klein, D.J., Fells, J., Holloway, K., Wu, J., Wu, G., Howell, B.J., Barnard, R.J.O., Kozlowski, J.

(2020) Bioorg Med Chem Lett 30: 127197-127197

  • DOI: https://doi.org/10.1016/j.bmcl.2020.127197
  • Primary Citation of Related Structures:  
    6WBW, 6WBZ

  • PubMed Abstract: 

    A novel series of ethyl ketone based HDACs 1, 2, and 3 selective inhibitors have been identified with good enzymatic and cellular activity and high selectivity over HDACs 6 and 8. These inhibitors contain a spirobicyclic group in the amide region. Compound 13 stands out as a lead due to its good potency, high selectivity, and reasonable rat and dog PK. Compounds 33 and 34 show good potency and rat PK profiles as well.

    • Organizational Affiliation: 

    Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: [email protected].


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Histone deacetylase 2
A, B, C
376Homo sapiensMutation(s): 0 
Gene Names: HDAC2
EC: 3.5.1.98 (PDB Primary Data), 3.5.1 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for Q92769 (Homo sapiens)
Explore Q92769 
Go to UniProtKB:  Q92769
PHAROS:  Q92769
GTEx:  ENSG00000196591 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ92769
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
TV1 (Subject of Investigation/LOI)
Query on TV1
Download Ideal Coordinates CCD File 
D [auth A],
K [auth B],
Q [auth C]		N-{(1S)-7,7-dihydroxy-1-[5-(2-methoxyquinolin-3-yl)-1H-imidazol-2-yl]nonyl}-1-methylazetidine-3-carboxamide
C27 H37 N5 O4
REZJYZJEUVOCFM-QFIPXVFZSA-N
PEG
Query on PEG
Download Ideal Coordinates CCD File 
H [auth A]
I [auth A]
J [auth A]
O [auth B]
P [auth B]
H [auth A],
I [auth A],
J [auth A],
O [auth B],
P [auth B],
U [auth C]
DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
ZN
Query on ZN
Download Ideal Coordinates CCD File 
E [auth A],
L [auth B],
R [auth C]		ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CA
Query on CA
Download Ideal Coordinates CCD File 
F [auth A]
G [auth A]
M [auth B]
N [auth B]
S [auth C]
F [auth A],
G [auth A],
M [auth B],
N [auth B],
S [auth C],
T [auth C]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.46 Å
  • R-Value Free: 0.197 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.173 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.97α = 90
b = 98.28β = 90
c = 139.05γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
Aimlessdata scaling
BUSTERphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2020-05-06
    Type: Initial release
  • Version 1.1: 2020-06-03
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references, Derived calculations