3DD8: Carbonic Anhydrase Inhibitors. Interaction Of The Antitumor Sulfamate Emd-486019 With Twelve Mammalian Isoforms: Kinetic And X-ray Crystallographic Studies

The new antitumor sulfamate EMD 486019 was investigated for its interaction with twelve catalytically active mammalian carbonic anhydrase (CA, EC isozymes, hCA I - XIV. Similarly to 667-Coumate, a structurally related compound in phase II clinical trials as steroid sulfatase/CA inhibitor with potent antitumor properties, EMD 486019 acts as a strong inhibitor of isozymes CA II, VB, VII, IX, XII, and XIV (K(I)s in the range of 13-19nM) being less effective against other isozymes (K(I)s in the range of 66-3600nM against hCA I, IV, VA, VI, and mCA XIII, respectively). The complete inhibition profile of 667-Coumate against these mammalian CAs is also reported here for the first time. Comparing the X-ray crystal structures of the two adducts of CA II with EMD 486019 and 667-Coumate, distinct orientations of the bound sulfamates within the enzyme cavity were observed, which account for their distinct inhibition profiles. CA II/IX potent inhibitors belonging to the sulfamate class are thus valuable clinical candidates with potential for development as antitumor agents with a multifactorial mechanism of action.
PDB ID: 3DD8Download
MMDB ID: 66043
PDB Deposition Date: 2008/6/5
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 1.9  Å
Similar Structures:
Biological Unit for 3DD8: monomeric; determined by author and by software (PISA)
Molecular Components in 3DD8
Label Count Molecule
Protein (1 molecule)
Carbonic Anhydrase 2(Gene symbol: CA2)
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB