4M2R

Human Carbonic Anhydrase II in complex with Brinzolamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.174 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural study of interaction between brinzolamide and dorzolamide inhibition of human carbonic anhydrases.

Pinard, M.A.Boone, C.D.Rife, B.D.Supuran, C.T.McKenna, R.

(2013) Bioorg Med Chem 21: 7210-7215

  • DOI: https://doi.org/10.1016/j.bmc.2013.08.033
  • Primary Citation of Related Structures:  
    4M2R, 4M2U, 4M2V, 4M2W

  • PubMed Abstract: 

    Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes that catalyze the reversible hydration of carbon dioxide and bicarbonate. Their pivotal role in metabolism, ubiquitous nature, and multiple isoforms (CA I-XIV) has made CAs an attractive drug target in clinical applications. The usefulness of CA inhibitors (CAIs) in the treatment of glaucoma and epilepsy are well documented. In addition several isoforms of CAs (namely, CA IX) also serve as biological markers for certain tumors, and therefore they have the potential for useful applications in the treatment of cancer. This is a structural study on the binding interactions of the widely used CA inhibitory drugs brinzolamide (marketed as Azopt®) and dorzolamide (marketed as Trusopt®) with CA II and a CA IX-mimic, which was created via site-directed mutagenesis of CA II cDNA such that the active site resembles that of CA IX. Also the inhibition of CA II and CA IX and molecular docking reveal brinzolamide to be a more potent inhibitor among the other catalytically active CA isoforms compared to dorzolamide. The structures show that the tail end of the sulfonamide inhibitor is critical in forming stabilizing interactions that influence tight binding; therefore, for future drug design it is the tail moiety that will ultimately determine isoform specificity.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 2257Homo 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
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
BZ1
Query on BZ1

Download Ideal Coordinates CCD File 
C [auth A](+)-4-ETHYLAMINO-3,4-DIHYDRO-2-(METHOXY)PROPYL-2H-THIENO[3,2-E]-1,2-THIAZINE-6-SULFONAMIDE-1,1-DIOXIDE
C12 H21 N3 O5 S3
HCRKCZRJWPKOAR-JTQLQIEISA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
BZ1 BindingDB:  4M2R Ki: min: 0.13, max: 45 (nM) from 6 assay(s)
Kd: min: 0.09, max: 0.13 (nM) from 3 assay(s)
IC50: min: 3.2, max: 45 (nM) from 2 assay(s)
PDBBind:  4M2R Ki: 3.2 (nM) from 1 assay(s)
Binding MOAD:  4M2R Ki: 3.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.174 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.837α = 90
b = 42.163β = 104.76
c = 72.643γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-11-06
    Type: Initial release
  • Version 1.1: 2017-11-15
    Changes: Advisory, Refinement description
  • Version 1.2: 2024-02-28
    Changes: Advisory, Data collection, Database references, Derived calculations