3IGP

Structure of inhibitor binding to Carbonic Anhydrase II

3IGP の概要

• エントリーDOI: 10.2210/pdb3igp/pdb
• 分子名称: Carbonic anhydrase 2, ZINC ION, 6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-sulfonamide, ... (5 entities in total)
• 機能のキーワード: carbonic anhydrase inhibitors, isoquinolines, lyase, acetylation, cytoplasm, disease mutation, metal-binding, polymorphism, zinc
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 30083.30

構造登録者

Gitto, R.,Agnello, S.,Brynda, J.,Mader, P.,Supuran, C.T.,Chimirri, A. (登録日: 2009-07-28, 公開日: 2010-03-09, 最終更新日: 2023-11-01)

主引用文献

Gitto, R.,Agnello, S.,Ferro, S.,De Luca, L.,Vullo, D.,Brynda, J.,Mader, P.,Supuran, C.T.,Chimirri, A.
Identification of 3,4-Dihydroisoquinoline-2(1H)-sulfonamides as Potent Carbonic Anhydrase Inhibitors: Synthesis, Biological Evaluation, and Enzyme-Ligand X-ray Studies.
J.Med.Chem., 2010

PubMed Abstract: Following previous studies we herein report the exploration of the carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects and enzyme selectivity of a small class of 1-(cyclo)alkylisoquinolines containing a sulfonamide function considered a key feature for inhibiting CA. The results of enzymatic assays against human (h) CA isoforms, hCA I and hCA II (cytosolic, ubiquitous enzymes), hCA IX (transmembrane, tumor-associated), and hCA XIV (transmembrane), suggested that the presence of C-1 small substituents on isoquinoline scaffold controls both inhibitory potency and selectivity. Some derivatives showed potent hCA IX and hCA XIV inhibitory effects at nanomolar concentrations as well as low affinity for the ubiquitous hCA II. Moreover, we report the X-ray crystal structure of one of these derivatives in complex with dominant human isoform II, thus confirming the sulfonamide--zinc interactions. Finally, the results of docking experiments suggested the hypothetic interactions in the catalytic binding site for the most active and selective hCA IX and hCA XIV inhibitor.

PubMed: 20170095
DOI: 10.1021/jm9014026

実験手法

X-RAY DIFFRACTION (1.65 Å)