5G03

An unusual natural product primary sulfonamide: synthesis, carbonic anhydrase inhibition and protein x-ray structure of Psammaplin C


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.35 Å
  • R-Value Free: 0.160 
  • R-Value Work: 0.128 
  • R-Value Observed: 0.129 

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This is version 1.3 of the entry. See complete history


Literature

An Unusual Natural Product Primary Sulfonamide: Synthesis, Carbonic Anhydrase Inhibition and Protein X-Ray Structures of Psammaplin C.

Mujumdar, P.Teruya, K.Tonissen, K.F.Vullo, D.Supuran, C.T.Peat, T.S.Poulsen, S.

(2016) J Med Chem 59: 5462

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b00443
  • Primary Citation of Related Structures:  
    5A6H, 5G01, 5G03, 5G0B, 5G0C

  • PubMed Abstract: 

    Psammaplin C is one of only two described natural product primary sulfonamides. Here we report the synthesis of psammaplin C and evaluate the inhibition profile against therapeutically relevant carbonic anhydrase (CA) zinc metalloenzymes. The compound exhibited unprecedented inhibition of an important cancer-associated isozyme, hCA XII, with a Ki of 0.79 nM. The compound also displayed good isoform selectivity for hCA XII over other CAs. We present the first reported protein X-ray crystal structures of psammaplin C in complex with human CAs. We engineered the easily crystallized hCA II enzyme to mimic both the hCA IX and hCA XII binding sites and then utilized protein X-ray crystallography to determine the binding pose of psammaplin C within the hCA II, hCA IX, and hCA XII mimic active sites, all to high resolution. This is the first time a natural product primary sulfonamide inhibitor has been assessed for inhibition and binding to CAs.


  • Organizational Affiliation

    Eskitis Institute for Drug Discovery, Griffith University , Don Young Road, Nathan, Queensland 4111, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CARBONIC ANHYDRASE 2260Homo sapiensMutation(s): 10 
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
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
SO4 BindingDB:  5G03 Ki: min: 8.90e+7, max: 3.00e+8 (nM) from 4 assay(s)
OE2 BindingDB:  5G03 Ki: 88 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.35 Å
  • R-Value Free: 0.160 
  • R-Value Work: 0.128 
  • R-Value Observed: 0.129 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.88α = 90
b = 41.28β = 104.11
c = 71.788γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
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: 2016-05-25
    Type: Initial release
  • Version 1.1: 2016-06-22
    Changes: Database references
  • Version 1.2: 2019-05-08
    Changes: Data collection, Experimental preparation, Other
  • Version 1.3: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description