3C7P

Crystal structure of human carbonic anhydrase II in complex with STX237

3C7P の概要

• エントリーDOI: 10.2210/pdb3c7p/pdb
• 関連するPDBエントリー: 2gd8 3bet
• 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, disease mutation, lyase, metal-binding
• 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: 30273.27

構造登録者

Di Fiore, A.,De Simone, G. (登録日: 2008-02-08, 公開日: 2009-01-13, 最終更新日: 2023-11-01)

主引用文献

Woo, L.W.L.,Fischer, D.S.,Sharland, C.M.,Trusselle, M.,Foster, P.A.,Chander, S.K.,Di Fiore, A.,Supuran, C.T.,De Simone, G.,Purohit, A.,Reed, M.J.,Potter, B.V.L.
Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-generation agent, in vitro and in vivo activities, molecular modeling, and protein crystallography
Mol.Cancer Ther., 7:2435-2444, 2008

PubMed Abstract: An improved steroid sulfatase inhibitor was prepared by replacing the N-propyl group of the second-generation steroid-like inhibitor (2) with a N-3,3,3-trifluoropropyl group to give (10). This compound is 5-fold more potent in vitro, completely inhibits rat liver steroid sulfatase activity after a single oral dose of 0.5 mg/kg, and exhibits a significantly longer duration of inhibition over (2). These biological properties are attributed to the increased lipophilicity and metabolic stability of (10) rendered by its trifluoropropyl group and also the potential H-bonding between its fluorine atom(s) and Arg(98) in the active site of human steroid sulfatase. Like other sulfamates, (10) is expected to be sequestered, and transported by, erythrocytes in vivo because it inhibits human carbonic anhydrase II (hCAII) potently (IC(50), 3 nmol/L). A congener (4), which possesses a N-(pyridin-3-ylmethyl) substituent, is even more active (IC(50), 0.1 nmol/L). To rationalize this, the hCAII-(4) adduct, obtained by cocrystallization, reveals not only the sulfamate group and the backbone of (4) interacting with the catalytic site and the associated hydrophobic pocket, respectively, but also the potential H-bonding between the N-(pyridin-3-ylmethyl) group and Nepsilon(2) of Gln(136). Like (2), both (10) and its phenolic precursor (9) are non-estrogenic using a uterine weight gain assay. In summary, a highly potent, long-acting, and nonestrogenic steroid sulfatase inhibitor was designed with hCAII inhibitory properties that should positively influence in vivo behavior. Compound (10) and other related inhibitors of this structural class further expand the armory of steroid sulfatase inhibitors against hormone-dependent breast cancer.

PubMed: 18723489
DOI: 10.1158/1535-7163.MCT-08-0195

実験手法

X-RAY DIFFRACTION (1.7 Å)