5FL6

Three dimensional structure of human carbonic anhydrase IX in complex with 5-(1-(4-Methylphenyl)-1H-1,2,3-triazol-4-yl)thiophene-2- sulfonamide

5FL6 の概要

• エントリーDOI: 10.2210/pdb5fl6/pdb
• 関連するPDBエントリー: 5FL4 5FL5
• 分子名称: CARBONIC ANHYDRASE IX, 5-[1-(4-methylphenyl)-1,2,3-triazol-4-yl]thiophene-2-sulfonamide, ZINC ION, ... (6 entities in total)
• 機能のキーワード: lyase, carbonic anhydrase ix, carbonic anhydrase 9, ca ix, ca 9
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 114722.41

構造登録者

Leitans, J.,Tars, K.,Zalubovskis, R. (登録日: 2015-10-21, 公開日: 2015-11-11, 最終更新日: 2024-10-23)

主引用文献

Leitans, J.,Kazaks, A.,Balode, A.,Ivanova, J.,Zalubovskis, R.,Supuran, C.T.,Tars, K.
An Efficient Expression and Crystallization System of the Cancer Asociated Carbonic Anhydrase Isoform Ix.
J.Med.Chem., 58:9004-, 2015

PubMed Abstract: Human carbonic anhydrase IX (CA IX) is overexpressed in a number of solid tumors and is considered to be a marker for cellular hypoxia that it is not produced in most normal tissues. CA IX contributes to the acidification of the extracellular matrix, which, in turn, favors tumor growth and metastasis. Therefore, CA IX is considered to be a promising anti-cancer drug target. However, the ability to specifically target CA IX is challenging due to the fact that the human genome encodes 15 different carbonic anhydrase isoforms that have a high degree of homology. Furthermore, structure-based drug design of CA IX inhibitors so far has been largely unsuccessful due to technical difficulties regarding the expression and crystallization of the enzyme. Currently, only one baculovirus-produced CA IX structure in complex with a nonspecific CA inhibitor, acetazolamide, is available in Protein Data Bank. We have developed an efficient system for the production of the catalytic domain of CA IX in methylotrophic yeast Pichia pastoris. The produced protein can be easily crystallized in the presence of inhibitors, as we have demonstrated for several 2-thiophene-sulfonamide compounds. We have also observed significant differences in the binding mode of chemically identical compounds to CA IX and CA II, which can be further exploited in the design of CA IX-specific inhibitors.

PubMed: 26522624
DOI: 10.1021/ACS.JMEDCHEM.5B01343

実験手法

X-RAY DIFFRACTION (1.95 Å)