2AW1

Carbonic anhydrase inhibitors: Valdecoxib binds to a different active site region of the human isoform II as compared to the structurally related cyclooxygenase II "selective" inhibitor Celecoxib


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.46 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.185 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Carbonic anhydrase inhibitors: Valdecoxib binds to a different active site region of the human isoform II as compared to the structurally related cyclooxygenase II

Di Fiore, A.Pedone, C.D'Ambrosio, K.Scozzafava, A.De Simone, G.Supuran, C.T.

(2006) Bioorg Med Chem Lett 16: 437-442

  • DOI: https://doi.org/10.1016/j.bmcl.2005.09.040
  • Primary Citation of Related Structures:  
    2AW1

  • PubMed Abstract: 

    The high resolution X-ray crystal structure of the adduct of human carbonic anhydrase (CA, EC 4.2.1.1) isoform II (hCA II) with the clinically used painkiller valdecoxib, acting as a potent CA II and cyclooxygenase-2 (COX-2) inhibitor, is reported. The ionized sulfonamide moiety of valdecoxib is coordinated to the catalytic Zn(II) ion with a tetrahedral geometry. The phenyl-isoxazole moiety of the inhibitor fills the active site channel and interacts with the side chains of Gln92, Val121, Leu198, Thr200, and Pro202. Its 3-phenyl group is located into a hydrophobic pocket, simultaneously establishing van der Waals interactions with the aliphatic side chain of various hydrophobic residues (Val135, Ile91, Val121, Leu198, and Leu141) and a strong offset face-to-face stacking interaction with the aromatic ring of Phe131 (the chi1 angle of which is rotated about 90 degrees with respect to what was observed in the structure of the native enzyme and those of other sulfonamide complexes). Celecoxib, a structurally related COX-2 inhibitor for which the X-ray crystal structure was reported earlier, binds in a completely different manner to hCA II as compared to valdecoxib. Celecoxib completely fills the entire CA II active site, with its trifluoromethyl group in the hydrophobic part of the active site and the p-tolyl moiety in the hydrophilic one, not establishing any interaction with Phe131. In contrast to celecoxib, valdecoxib was rotated about 90 degrees around the chemical bond connecting the benzensulfonamide and the substituted isoxazole ring allowing for these multiple favorable interactions. These different binding modes allow for the further drug design of various CA inhibitors belonging to the benzenesulfonamide class.


  • Organizational Affiliation

    Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Naples, Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase II259Homo 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
COX Binding MOAD:  2AW1 Ki: 43 (nM) from 1 assay(s)
PDBBind:  2AW1 Ki: 43 (nM) from 1 assay(s)
BindingDB:  2AW1 Ki: min: 43, max: 4.30e+4 (nM) from 2 assay(s)
IC50: 43 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.46 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.185 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.051α = 90
b = 41.32β = 104.26
c = 71.765γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
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: 2006-07-04
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.3: 2023-10-25
    Changes: Data collection, Database references, Derived calculations, Refinement description