3IEO

The coumarin-binding site in carbonic anhydrase: the antiepileptic lacosamide as an example

3IEO の概要

• エントリーDOI: 10.2210/pdb3ieo/pdb
• 関連するPDBエントリー: 3F8E
• 分子名称: Carbonic anhydrase 2, ZINC ION, MERCURY (II) ION, ... (6 entities in total)
• 機能のキーワード: carbonic anhydrase, antiepilectic, disease mutation, lyase, metal-binding, 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: 30128.07

構造登録者

Temperini, C.,Innocenti, A.,Scozzafava, A.,Parkkila, S.,Supuran, C.T. (登録日: 2009-07-23, 公開日: 2010-01-26, 最終更新日: 2023-11-01)

主引用文献

Temperini, C.,Innocenti, A.,Scozzafava, A.,Parkkila, S.,Supuran, C.T.
The coumarin-binding site in carbonic anhydrase accommodates structurally diverse inhibitors: the antiepileptic lacosamide as an example and lead molecule for novel classes of carbonic anhydrase inhibitors
J.Med.Chem., 53:850-854, 2010

PubMed Abstract: Coumarins constitute a general and totally new class of inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), binding at the entrance of the active site cavity. We report here that the coumarin-binding site in CAs may interact with diverse compounds, such as the antiepileptic drug lacosamide, which inhibits mammalian CAs I-XV, with inhibition constants in range of 331 nM to 4.56 microM. Its X-ray crystal structure in adduct with CA II reveals the molecular basis for this inhibition. Lacosamide was found in the coumarin-binding site, making favorable van der Waals interactions with Thr200, Asn67, Gln92, and Phe131. No interactions with the Zn(II) ion were evidenced in the CA II-lacosamide adduct. The coumarin-binding site may thus accommodate structurally diverse compounds which possess an inhibition mechanism distinct of that of sulfonamides. This finding opens new possibilities for designing CA inhibitors/activators with various biomedical applications.

PubMed: 20028100
DOI: 10.1021/jm901524f

実験手法

X-RAY DIFFRACTION (2 Å)