3ML2

Human carbonic anhydsase II in complex with an aryl sulfonamide inhibitor

3ML2 の概要

• エントリーDOI: 10.2210/pdb3ml2/pdb
• 関連するPDBエントリー: 3MMF
• 分子名称: Carbonic anhydrase 2, ZINC ION, 2-(7-methoxy-2-oxo-2H-chromen-4-yl)-N-(4-sulfamoylphenyl)acetamide, ... (5 entities in total)
• 機能のキーワード: zinc metalloenzyme, metal-binding, lyase, sulfonamide, zinc ligands, inhibitor, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• 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: 29834.96

構造登録者

Avvaru, B.S.,Wagner, J.,Robbins, A.H.,Mckenna, R. (登録日: 2010-04-16, 公開日: 2011-04-20, 最終更新日: 2023-09-06)

主引用文献

Wagner, J.,Avvaru, B.S.,Robbins, A.H.,Scozzafava, A.,Supuran, C.T.,McKenna, R.
Coumarinyl-substituted sulfonamides strongly inhibit several human carbonic anhydrase isoforms: solution and crystallographic investigations.
Bioorg.Med.Chem., 18:4873-4878, 2010

PubMed Abstract: We investigated a series of coumarinyl-substituted aromatic sulfonamides as inhibitors of four carbonic anhydrase (CA, EC 4.2.1.1) isoforms with medical applications, the cytosolic hCA I, and II, and the transmembrane, tumor-associated hCA IX and XII. Compounds incorporating 7-methoxy-coumarin-4-yl-acetamide-tails and benzenesulfonamide and benzene-1,3-disulfonamide scaffolds showed medium potency inhibition of hCA I (KIs of 73-131 nM), effective hCA II inhibition (KIs of 9.1-36 nM) and less effective hCA IX and XII inhibition (KIs of 55-128 nM). Only one compound, the derivatized 4-amino-6-trifluoromethyl-benzene-1,3-disulfonamide with the coumarinyl tail, showed effective inhibition of the transmembrane isoforms, with KIs of 5.9-14.2 nM, although it was less effective as hCA I and II inhibitor (KIs of 36-120 nM). An X-ray crystal structure of hCA II in complex with 4-(7-methoxy-coumarin-4-yl-acetamido)-benzenesulfonamide (KI of 9.1 nM against hCA II) showed the intact inhibitor coordinated to the zinc ion from the enzyme active site by the sulfonamide moiety, and participating in a edge-to-face stacking with Phe131, in addition to other hydrophobic and hydrophilic interactions with water molecules and amino acid residues from the active site. Thus, sulfonamides incorporating coumarin rings have a distinct inhibition mechanism compared to the coumarins, and may lead to compounds with interesting inhibition profiles against various alpha-CAs found in mammals or parasites, such as Plasmodium falciparum.

PubMed: 20598552
DOI: 10.1016/j.bmc.2010.06.028

実験手法

X-RAY DIFFRACTION (1.8 Å)