5GMM

Crystal structure of human Carbonic anhydrase I in complex with polmacoxib

5GMM の概要

• エントリーDOI: 10.2210/pdb5gmm/pdb
• 関連するPDBエントリー: 5GMN
• 分子名称: Carbonic anhydrase 1, ZINC ION, 4-[3-(3-fluorophenyl)-5,5-dimethyl-4-oxidanylidene-furan-2-yl]benzenesulfonamide, ... (4 entities in total)
• 機能のキーワード: lyase, inhibitor, complex
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 60176.92

構造登録者

Kim, H.T.,Hwang, K.Y. (登録日: 2016-07-14, 公開日: 2017-05-24, 最終更新日: 2023-11-08)

主引用文献

Kim, H.T.,Cha, H.,Hwang, K.Y.
Structural insight into the inhibition of carbonic anhydrase by the COX-2-selective inhibitor polmacoxib (CG100649).
Biochem. Biophys. Res. Commun., 478:1-6, 2016

PubMed Abstract: Polmacoxib is not only a selective COX-2 inhibitor but also a potent inhibitor of carbonic anhydrases (CAs). Both CA I and CA II are highly expressed in the GI tract and kidneys, organs that are also thought to be the sites at which selective COX-2 inhibitors show their side effects. By inhibition assays, we show that both CA I and CA II are strongly inhibited by polmacoxib, while CA II also demonstrates direct competition with COX-2. To understand, at the molecular level, how polmacoxib interacts with CA I and II, we solved the first crystal structures of CA I and CA II in complex with polmacoxib, at 2.0 Å and 1.8 Å, respectively. Interestingly, three polmacoxib molecules bind to the active site of CA I, whereas only one molecule binds CA II. In the active site, the three molecules of polmacoxib organize itself along hydrophobic interaction as "stack-on-formation", and fully occupy a cone-shaped active pocket in CA I. The binding mode of polmacoxib to CA II was found different than its binding to celecoxib and valdecoxib. Our results provide structural insight into inhibition of CA I and CA II by polmacoxib, to assess its potential clinical efficacy.

PubMed: 27475498
DOI: 10.1016/j.bbrc.2016.07.114

実験手法

X-RAY DIFFRACTION (2.003 Å)