3KWA

Polyamines inhibit carbonic anhydrases


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.286 
  • R-Value Work: 0.233 
  • R-Value Observed: 0.236 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Polyamines inhibit carbonic anhydrases by anchoring to the zinc-coordinated water molecule

Carta, F.Temperini, C.Innocenti, A.Scozzafava, A.Kaila, K.Supuran, C.T.

(2010) J Med Chem 53: 5511-5522

  • DOI: https://doi.org/10.1021/jm1003667
  • Primary Citation of Related Structures:  
    3KWA

  • PubMed Abstract: 

    Carbonic anhydrases (CAs, EC 4.2.1.1) are inhibited by sulfonamides, phenols, and coumarins. Polyamines such as spermine, spermidine, and many synthetic congeners are described to constitute a novel class of CA inhibitors (CAIs), interacting with the different CA isozymes with efficiency from the low nanomolar to millimolar range. The main structure-activity relationship for these CAIs have been delineated: the length of the molecule, number of amine moieties, and their functionalization are the main parameters controlling activity. The X-ray crystal structure of the CA II-spermine adduct allowed understanding of the inhibition mechanism. Spermine anchors to the nonprotein zinc ligand through a network of hydrogen bonds. Its distal amine moiety makes hydrogen bonds with residues Thr200 and Pro201, which further stabilize the adduct. Spermine binds differently compared to sulfonamides, phenols, or coumarins, rendering possible to develop CAIs with a diverse inhibition mechanism, profile, and selectivity for various isoforms.


  • Organizational Affiliation

    Universita degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Sesto Fiorentino (Florence), Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 2260Homo 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
SPM PDBBind:  3KWA Ki: 8.40e+4 (nM) from 1 assay(s)
BindingDB:  3KWA Ki: 8.40e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.286 
  • R-Value Work: 0.233 
  • R-Value Observed: 0.236 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.43α = 90
b = 42.16β = 104.3
c = 72.25γ = 90
Software Package:
Software NamePurpose
CrysalisProdata collection
AMoREphasing
REFMACrefinement
CrysalisProdata reduction
SCALEPACKdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-07-14
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Refinement description
  • Version 1.3: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description