4RFD

Human carbonic anhydrase II in complex with 4-(4-sulfamoyl-phenoxy)-butylammonium


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.63 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.180 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

A class of 4-sulfamoylphenyl-omega-aminoalkyl ethers with effective carbonic anhydrase inhibitory action and antiglaucoma effects.

Bozdag, M.Pinard, M.Carta, F.Masini, E.Scozzafava, A.McKenna, R.Supuran, C.T.

(2014) J Med Chem 57: 9673-9686

  • DOI: https://doi.org/10.1021/jm501497m
  • Primary Citation of Related Structures:  
    4RFC, 4RFD

  • PubMed Abstract: 

    We report a series of 4-sulfamoylphenyl-ω-aminoalkyl ethers as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The structure-activity relationship was drawn for the inhibition of four physiologically relevant isoforms: hCA I, II, IX, and XII. Many of these compounds were highly effective, low nanomolar inhibitors of all CA isoforms, whereas several isoform-selective were also identified. X-ray crystal structures of two new sulfonamides bound to the physiologically dominant CA II isoform showed the tails of these derivatives bound within the hydrophobic half of the enzyme active site through van der Waals contacts with Val135, Leu198, Leu204, Trp209, Pro201, and Pro202 amino acids. One of the highly water-soluble compound (as trifluoroacetate salt) showed effective IOP lowering properties in an animal model of glaucoma. Several fluorescent sulfonamides incorporating either the fluorescein-thiourea (7a-c) or tetramethylrhodamine-thiourea (9a,b) moieties were also obtained and showed interesting CA inhibitory properties for the tumor-associated isoforms CA IX and XII.


  • Organizational Affiliation

    Polo Scientifico, Neurofarba Department and Laboratorio di Chimica Bioinorganica, Rm 188, Università degli Studi di Firenze , Via della Lastruccia 3, Sesto Fiorentino, Florence 50019, Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 2260Homo sapiensMutation(s): 0 
Gene Names: CA2
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
3O5 Binding MOAD:  4RFD Ki: 8.9 (nM) from 1 assay(s)
BCT BindingDB:  4RFD Ki: min: 7.30e+7, max: 8.50e+7 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.63 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.180 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.454α = 90
b = 41.344β = 104.29
c = 72.127γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-04-15
    Type: Initial release
  • Version 1.1: 2017-11-22
    Changes: Refinement description
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations