5SZ4

Carbonic anhydrase IX-mimic in complex with 4-(phenyl)-benzenesulfonamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.185 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure-Activity Relationships of Benzenesulfonamide-Based Inhibitors towards Carbonic Anhydrase Isoform Specificity.

Bhatt, A.Mahon, B.P.Cruzeiro, V.W.Cornelio, B.Laronze-Cochard, M.Ceruso, M.Sapi, J.Rance, G.A.Khlobystov, A.N.Fontana, A.Roitberg, A.Supuran, C.T.McKenna, R.

(2017) Chembiochem 18: 213-222

  • DOI: https://doi.org/10.1002/cbic.201600513
  • Primary Citation of Related Structures:  
    5SZ0, 5SZ1, 5SZ2, 5SZ3, 5SZ4, 5SZ5, 5SZ6, 5SZ7

  • PubMed Abstract: 

    Carbonic anhydrases (CAs) are implicated in a wide range of diseases, including the upregulation of isoforms CA IX and XII in many aggressive cancers. However, effective inhibition of disease-implicated CAs should minimally affect the ubiquitously expressed isoforms, including CA I and II, to improve directed distribution of the inhibitors to the cancer-associated isoforms and reduce side effects. Four benzenesulfonamide-based inhibitors were synthesized by using the tail approach and displayed nanomolar affinities for several CA isoforms. The crystal structures of the inhibitors bound to a CA IX mimic and CA II are presented. Further in silico modeling was performed with the inhibitors docked into CA I and XII to identify residues that contributed to or hindered their binding interactions. These structural studies demonstrated that active-site residues lining the hydrophobic pocket, especially positions 92 and 131, dictate the positional binding and affinity of inhibitors, whereas the tail groups modulate CA isoform specificity. Geometry optimizations were performed on each ligand in the crystal structures and showed that the energetic penalties of the inhibitor conformations were negligible compared to the gains from active-site interactions. These studies further our understanding of obtaining isoform specificity when designing small molecule CA inhibitors.


  • Organizational Affiliation

    Department of, Biochemistry and Molecular Biology, College of Medicine, University of Florida, P. O. 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): 7 
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
72D BindingDB:  5SZ4 Ki: min: 0.2, max: 0.8 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.185 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.93α = 90
b = 41.294β = 103.61
c = 72.504γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data collection
HKL-2000data scaling
PDB_EXTRACTdata extraction
HKL-2000data reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-12-21
    Type: Initial release
  • Version 1.1: 2017-02-01
    Changes: Database references
  • Version 1.2: 2017-09-27
    Changes: Data collection
  • Version 1.3: 2023-10-04
    Changes: Data collection, Database references, Refinement description