2HD6

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

2HD6 の概要

• エントリーDOI: 10.2210/pdb2hd6/pdb
• 関連するPDBエントリー: 1CA2
• 分子名称: Carbonic anhydrase 2, ZINC ION, CHLORIDE ION, ... (7 entities in total)
• 機能のキーワード: protein-inhibitor complex, lyase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P00918
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29980.90

構造登録者

De Simone, G.,Vitale, R.M.,Di Fiore, A.,Pedone, C. (登録日: 2006-06-20, 公開日: 2006-10-03, 最終更新日: 2023-08-30)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.8 Å)