2HD6

Crystal structure of the human carbonic anhydrase II in complex with a hypoxia-activatable sulfonamide.

Summary for 2HD6

• Entry DOI: 10.2210/pdb2hd6/pdb
• Related: 1CA2
• Descriptor: Carbonic anhydrase 2, ZINC ION, CHLORIDE ION, ... (7 entities in total)
• Functional Keywords: protein-inhibitor complex, lyase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P00918
• Total number of polymer chains: 1
• Total formula weight: 29980.90

Authors

De Simone, G.,Vitale, R.M.,Di Fiore, A.,Pedone, C. (deposition date: 2006-06-20, release date: 2006-10-03, Last modification date: 2023-08-30)

Primary citation

De Simone, G.,Vitale, R.M.,Di Fiore, A.,Pedone, C.,Scozzafava, A.,Montero, J.L.,Winum, J.Y.,Supuran, C.T.
Carbonic anhydrase inhibitors: Hypoxia-activatable sulfonamides incorporating disulfide bonds that target the tumor-associated isoform IX.
J.Med.Chem., 49:5544-5551, 2006

PubMed Abstract: An approach for designing bioreductive, hypoxia-activatable carbonic anhydrase (CA, EC 4.2.1.1) inhibitors targeting the tumor-associated isoforms is reported. Sulfonamides incorporating 3,3'-dithiodipropionamide/2,2'-dithiodibenzamido moieties were prepared and reduced enzymatically/chemically in conditions present in hypoxic tumors, leading to thiols. The X-ray crystal structure of the most promising compound, 4-(2-mercaptophenylcarboxamido)benzenesulfonamide, which as disulfide showed a K(I) against hCA IX of 653 nM (in reduced form of 9.1 nM), in adduct with hCA II showed the inhibitor making favorable interactions with Gln92, Val121, Phe131, Leu198, Thr199, Thr200, Pro201, and Pro202, whereas the sulfamoyl moiety was coordinated to the Zn2+ ion. The same interactions were preserved in the adduct with hCA IX, but in addition, a hydrogen bond between the SH moiety of the inhibitor and the amide nitrogen of Gln67 was evidenced, which may explain the almost 2 times more effective inhibition of the tumor-associated isozyme over the cytosolic isoform.

PubMed: 16942027
DOI: 10.1021/jm060531j

Experimental method

X-RAY DIFFRACTION (1.8 Å)