4ZAO

Genetically engineered Carbonic anhydrase IX

4ZAO の概要

• エントリーDOI: 10.2210/pdb4zao/pdb
• 関連するPDBエントリー: 4YMP
• 分子名称: Carbonic anhydrase 2, ZINC ION (3 entities in total)
• 機能のキーワード: ca ix mimic, lyase
• 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: 29266.30

構造登録者

Pinard, M.A.,Aggarwal, M. (登録日: 2015-04-13, 公開日: 2015-10-14, 最終更新日: 2024-03-06)

主引用文献

Pinard, M.A.,Aggarwal, M.,Mahon, B.P.,Tu, C.,McKenna, R.
A sucrose-binding site provides a lead towards an isoform-specific inhibitor of the cancer-associated enzyme carbonic anhydrase IX.
Acta Crystallogr F Struct Biol Commun, 71:1352-1358, 2015

PubMed Abstract: Human carbonic anhydrase (CA; EC 4.2.1.1) isoform IX (CA IX) is an extracellular zinc metalloenzyme that catalyzes the reversible hydration of CO2 to HCO3(-), thereby playing a role in pH regulation. The majority of normal functioning cells exhibit low-level expression of CA IX. However, in cancer cells CA IX is upregulated as a consequence of a metabolic transition known as the Warburg effect. The upregulation of CA IX for cancer progression has drawn interest in it being a potential therapeutic target. CA IX is a transmembrane protein, and its purification, yield and crystallization have proven challenging to structure-based drug design, whereas the closely related cytosolic soluble isoform CA II can be expressed and crystallized with ease. Therefore, we have utilized structural alignments and site-directed mutagenesis to engineer a CA II that mimics the active site of CA IX. In this paper, the X-ray crystal structure of this CA IX mimic in complex with sucrose is presented and has been refined to a resolution of 1.5 Å, an Rcryst of 18.0% and an Rfree of 21.2%. The binding of sucrose at the entrance to the active site of the CA IX mimic, and not CA II, in a non-inhibitory mechanism provides a novel carbohydrate moiety binding site that could be further exploited to design isoform-specific inhibitors of CA IX.

PubMed: 26457530
DOI: 10.1107/S2053230X1501239X

実験手法

X-RAY DIFFRACTION (1.8 Å)