2GD8

Crystal structure analysis of the human carbonic anhydrase II in complex with a 2-substituted estradiol bis-sulfamate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.46 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.195 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

2-substituted estradiol bis-sulfamates, multitargeted antitumor agents: synthesis, in vitro SAR, protein crystallography, and in vivo activity.

Leese, M.P.Leblond, B.Smith, A.Newman, S.P.Di Fiore, A.De Simone, G.Supuran, C.T.Purohit, A.Reed, M.J.Potter, B.V.

(2006) J Med Chem 49: 7683-7696

  • DOI: https://doi.org/10.1021/jm060705x
  • Primary Citation of Related Structures:  
    2GD8

  • PubMed Abstract: 

    The anticancer activities and SARs of estradiol-17-O-sulfamates and estradiol 3,17-O,O-bis-sulfamates (E2bisMATEs) as steroid sulfatase (STS) inhibitors and antiproliferative agents are discussed. Estradiol 3,17-O,O-bis-sulfamates 20 and 21, in contrast to the 17-O-monosulfamate 11, proved to be excellent STS inhibitors. 2-Substituted E2bisMATEs 21 and 23 additionally exhibited potent antiproliferative activity with mean graph midpoint values of 18-87 nM in the NCI 60-cell-line panel. 21 Exhibited antiangiogenic in vitro and in vivo activity in an early-stage Lewis lung model, and 23 dosed p.o. caused marked growth inhibition in a nude mouse xenograft tumor model. Modeling studies suggest that the E2bisMATEs and 2-MeOE2 share a common mode of binding to tubulin, though COMPARE analysis of activity profiles was negative. 21 was cocrystallized with carbonic anhydrase II, and X-ray crystallography revealed unexpected coordination of the 17-O-sulfamate of 21 to the active site zinc and a probable additional lower affinity binding site. 2-Substituted E2bisMATEs are attractive candidates for further development as multitargeted anticancer agents.


  • Organizational Affiliation

    Medicinal Chemistry, Department of Pharmacy and Pharmacology & Sterix Ltd., University of Bath, Bath BA2 7AY, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 2259Homo sapiensMutation(s): 0 
EC: 4.2.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00918 (Homo sapiens)
Explore P00918 
Go to UniProtKB:  P00918
PHAROS:  P00918
GTEx:  ENSG00000104267 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00918
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
CL BindingDB:  2GD8 Ki: min: 2.00e+8, max: 2.00e+8 (nM) from 2 assay(s)
PO1 BindingDB:  2GD8 Ki: 270 (nM) from 1 assay(s)
Kd: 3750 (nM) from 1 assay(s)
IC50: 379 (nM) from 1 assay(s)
Binding MOAD:  2GD8 IC50: 379 (nM) from 1 assay(s)
PDBBind:  2GD8 IC50: 39 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.46 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.195 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.13α = 90
b = 41.42β = 104.5
c = 72.08γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
CNSrefinement
CNSphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-02-06
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description