3DD8

Carbonic anhydrase inhibitors. Interaction of the antitumor sulfamate EMD-486019 with twelve mammalian isoforms: kinetic and X-Ray crystallographic studies

3DD8 の概要

• エントリーDOI: 10.2210/pdb3dd8/pdb
• 関連するPDBエントリー: 1TTM
• 分子名称: Carbonic anhydrase 2, ZINC ION, MERCURY (II) ION, ... (5 entities in total)
• 機能のキーワード: carbonic anhydrase, inhibitors, antiglaucoma, oao-acid, acetylation, cytoplasm, disease mutation, lyase, metal-binding, polymorphism, zinc
• 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: 29926.53

構造登録者

Temperini, C.,Innocenti, A.,Scozzafava, A.,Supuran, C.T. (登録日: 2008-06-05, 公開日: 2008-08-12, 最終更新日: 2023-11-01)

主引用文献

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

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: 18640037
DOI: 10.1016/j.bmcl.2008.06.105

実験手法

X-RAY DIFFRACTION (1.9 Å)