7SV8

Carbonic Anhydrase IX-mimic Complexed with 3-((2-((Furan-2-ylmethyl)(4-sulfamoylphenethyl)amino)-2-oxoethyl)(phenethyl)amino)propanoic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.39 Å
  • R-Value Free: 0.177 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.155 

Starting Model: experimental
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Literature

The three-tails approach as a new strategy to improve selectivity of action of sulphonamide inhibitors against tumour-associated carbonic anhydrase IX and XII.

Bonardi, A.Bua, S.Combs, J.Lomelino, C.Andring, J.Osman, S.M.Toti, A.Di Cesare Mannelli, L.Gratteri, P.Ghelardini, C.McKenna, R.Nocentini, A.Supuran, C.T.

(2022) J Enzyme Inhib Med Chem 37: 930-939

  • DOI: https://doi.org/10.1080/14756366.2022.2053526
  • Primary Citation of Related Structures:  
    7SUW, 7SUY, 7SV1, 7SV8

  • PubMed Abstract: 

    Human (h) carbonic anhydrase (CAs, EC 4.2.1.1) isoforms IX and XII were recently confirmed as anticancer targets against solid hypoxic tumours. The "three-tails approach" has been proposed as an extension of the forerunner "tail" and "dual-tail approach" to fully exploit the amino acid differences at the medium/outer active site rims among different hCAs and to obtain more isoform-selective inhibitors. Many three-tailed inhibitors (TTIs) showed higher selectivity against the tumour-associated isoforms hCA IX and XII with respect to the off-targets hCA I and II. X-ray crystallography studies were performed to investigate the binding mode of four TTIs in complex with a hCA IX mimic. The ability of the most potent and selective TTIs to reduce in vitro the viability of colon cancer (HT29), prostate adenocarcinoma (PC3), and breast cancer (ZR75-1) cell lines was evaluated in normoxic (21% O 2 ) and hypoxic (3% O 2 ) conditions demonstrating relevant anti-proliferative effects.


  • Organizational Affiliation

    Department NEUROFARBA - Pharmaceutical and Nutraceutical Section, University of Firenze, Florence, Italy.


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 (PDB Primary Data), 4.2.1.69 (UniProt)
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
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.39 Å
  • R-Value Free: 0.177 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.155 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.816α = 90
b = 41.575β = 103.76
c = 72.117γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2022-04-06
    Type: Initial release
  • Version 1.1: 2023-10-18
    Changes: Data collection, Refinement description