3DCC

Use of Carbonic Anhydrase II, IX Active-Site Mimic, for the Purpose of Screening Inhibitors for Possible Anti-Cancer Properties

3DCC の概要

• エントリーDOI: 10.2210/pdb3dcc/pdb
• 関連するPDBエントリー: 3D8W 3D9Z 3DAZ 3DBU 3DC3 3DC9 3DCS 3DCW 3DD0
• 分子名称: Carbonic anhydrase 2, ZINC ION, 5-(2-chlorophenyl)-1,3,4-thiadiazole-2-sulfonamide, ... (4 entities in total)
• 機能のキーワード: carbonic anhydrase ii complex, caix mimic inhibitors, acetylation, cytoplasm, disease mutation, lyase, metal-binding, polymorphism, zinc
• 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: 29660.23

構造登録者

Genis, C.,Sippel, K.H.,Case, N.,Govindasamy, L.,Agbandje-Mckenna, M.,Mckenna, R. (登録日: 2008-06-03, 公開日: 2009-03-03, 最終更新日: 2023-08-30)

主引用文献

Genis, C.,Sippel, K.H.,Case, N.,Cao, W.,Avvaru, B.S.,Tartaglia, L.J.,Govindasamy, L.,Tu, C.,Agbandje-McKenna, M.,Silverman, D.N.,Rosser, C.J.,McKenna, R.
Design of a carbonic anhydrase IX active-site mimic to screen inhibitors for possible anticancer properties
Biochemistry, 48:1322-1331, 2009

PubMed Abstract: Recently, a convincing body of evidence has accumulated suggesting that the overexpression of carbonic anhydrase isozyme IX (CA IX) in some cancers contributes to the acidification of the extracellular matrix, which in turn promotes the growth and metastasis of the tumor. These observations have made CA IX an attractive drug target for the selective treatment of certain cancers. Currently, there is no available X-ray crystal structure of CA IX, and this lack of availability has hampered the rational design of selective CA IX inhibitors. In light of these observations and on the basis of structural alignment homology, using the crystal structure of carbonic anhydrase II (CA II) and the sequence of CA IX, a double mutant of CA II with Ala65 replaced by Ser and Asn67 replaced by Gln has been constructed to resemble the active site of CA IX. This CA IX mimic has been characterized kinetically using (18)O-exchange and structurally using X-ray crystallography, alone and in complex with five CA sulfonamide-based inhibitors (acetazolamide, benzolamide, chlorzolamide, ethoxzolamide, and methazolamide), and compared to CA II. This structural information has been evaluated by both inhibition studies and in vitro cytotoxicity assays and shows a correlated structure-activity relationship. Kinetic and structural studies of CA II and CA IX mimic reveal chlorzolamide to be a more potent inhibitor of CA IX, inducing an active-site conformational change upon binding. Additionally, chlorzolamide appears to be cytotoxic to prostate cancer cells. This preliminary study demonstrates that the CA IX mimic may provide a useful model to design more isozyme-specific CA IX inhibitors, which may lead to development of new therapeutic treatments of some cancers.

PubMed: 19170619
DOI: 10.1021/bi802035f

実験手法

X-RAY DIFFRACTION (1.6 Å)