3DD8
Carbonic anhydrase inhibitors. Interaction of the antitumor sulfamate EMD-486019 with twelve mammalian isoforms: kinetic and X-Ray crystallographic studies
Summary for 3DD8
| Entry DOI | 10.2210/pdb3dd8/pdb |
| Related | 1TTM |
| Descriptor | Carbonic anhydrase 2, ZINC ION, MERCURY (II) ION, ... (5 entities in total) |
| Functional Keywords | carbonic anhydrase, inhibitors, antiglaucoma, oao-acid, acetylation, cytoplasm, disease mutation, lyase, metal-binding, polymorphism, zinc |
| Cellular location | Cytoplasm : P00918 |
| Total number of polymer chains | 1 |
| Total formula weight | 29926.53 |
| Authors | Temperini, C.,Innocenti, A.,Scozzafava, A.,Supuran, C.T. (deposition date: 2008-06-05, release date: 2008-08-12, Last modification date: 2023-11-01) |
| Primary citation | Temperini, C.,Innocenti, A.,Scozzafava, A.,Supuran, C.T. Carbonic anhydrase inhibitors. Interaction of the antitumor sulfamate EMD 486019 with twelve mammalian carbonic anhydrase isoforms: Kinetic and X-ray crystallographic studies Bioorg.Med.Chem.Lett., 18:4282-4286, 2008 Cited by PubMed Abstract: The new antitumor sulfamate EMD 486019 was investigated for its interaction with twelve catalytically active mammalian carbonic anhydrase (CA, EC 4.2.1.1) 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. PubMed: 18640037DOI: 10.1016/j.bmcl.2008.06.105 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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