6UGR

Human Carbonic Anhydrase 2 complexed with SB4-208


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.31 Å
  • R-Value Free: 0.165 
  • R-Value Work: 0.151 
  • R-Value Observed: 0.152 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

"A Sweet Combination": Developing Saccharin and Acesulfame K Structures for Selectively Targeting the Tumor-Associated Carbonic Anhydrases IX and XII.

Bua, S.Lomelino, C.Murray, A.B.Osman, S.M.ALOthman, Z.A.Bozdag, M.Abdel-Aziz, H.A.Eldehna, W.M.McKenna, R.Nocentini, A.Supuran, C.T.

(2020) J Med Chem 63: 321-333

  • DOI: https://doi.org/10.1021/acs.jmedchem.9b01669
  • Primary Citation of Related Structures:  
    6U4Q, 6U4T, 6UGN, 6UGO, 6UGP, 6UGQ, 6UGR, 6UGZ, 6UH0

  • PubMed Abstract: 

    The sweeteners saccharin ( SAC ) and acesulfame K ( ACE ) recently entered the topic of anticancer human carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, as they showed to selectively inhibit the tumor-associated CAs IX/XII over ubiquitous CAs. A drug design strategy is here reported, which took SAC and ACE as leads and produced a series of 2 H -benzo[ e ][1,2,4]thiadiazin-3(4 H )-one-1,1-dioxides ( BTD ). Many derivatives showed greater potency ( K I s-CA IX 19.1-408.5 nM) and selectivity (II/IX SI 2-76) than the leads ( K I s-CA IX 103, 2400 nM; II/IX-SI 56, >4) against CA IX/XII over off-target isoforms. A thorough X-ray crystallographic study depicted their binding mode to both CA II and IX-mimic. The most representative BTDs were characterized in vitro for their antitumor activity against A549, PC-3, and HCT-116 cancer cell lines both in normoxia and hypoxia. The two most effective compounds were assayed for their effect on several apoptosis markers, identifying promising leads for the development of new anticancer drugs.


  • Organizational Affiliation

    Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences , University of Florence , via Ugo Schiff 6 , 50019 Sesto Fiorentino, Florence , Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 2257Homo sapiensMutation(s): 0 
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
Q71 (Subject of Investigation/LOI)
Query on Q71

Download Ideal Coordinates CCD File 
C [auth A]7-fluoro-1lambda~6~,2,4-benzothiadiazine-1,1,3(2H,4H)-trione
C7 H5 F N2 O3 S
ITUAGWGFDMMEMY-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
Q71 Binding MOAD:  6UGR Ki: 533.6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.31 Å
  • R-Value Free: 0.165 
  • R-Value Work: 0.151 
  • R-Value Observed: 0.152 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.279α = 90
b = 41.279β = 104.14
c = 71.939γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-12-18
    Type: Initial release
  • Version 1.1: 2020-01-22
    Changes: Database references
  • Version 1.2: 2023-10-11
    Changes: Data collection, Database references, Refinement description