4R5A

A Carbonic Anhydrase IX Mimic in Complex with a Carbohydrate-Based Sulfamate

4R5A の概要

• エントリーDOI: 10.2210/pdb4r5a/pdb
• 関連するPDBエントリー: 4R59 4R5B
• 分子名称: Carbonic anhydrase 2, ZINC ION, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: carbonic anhydrase ix mimic, lyase
• 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: 29791.82

構造登録者

Mahon, B.P.,McKenna, R. (登録日: 2014-08-20, 公開日: 2014-10-15, 最終更新日: 2024-10-09)

主引用文献

Moeker, J.,Mahon, B.P.,Bornaghi, L.F.,Vullo, D.,Supuran, C.T.,McKenna, R.,Poulsen, S.A.
Structural Insights into Carbonic Anhydrase IX Isoform Specificity of Carbohydrate-Based Sulfamates.
J.Med.Chem., 57:8635-8645, 2014

PubMed Abstract: Carbonic anhydrase IX (CA IX) is an extracellular transmembrane homodimeric zinc metalloenzyme that has been validated as a prognostic marker and therapeutic target for several types of aggressive cancers. CA IX shares a close homology with other CA isoforms, making the design of CA IX isoform selective inhibitors challenging. In this paper, we describe the development of a new class of CA IX inhibitors that comprise a sulfamate as the zinc binding group, a variable linker, and a carbohydrate "tail" moiety. Seven compounds inhibited CA IX with low nM Ki values of 1-2 nM and also exhibited permeability profiles to preferentially target the binding of extracellular CA IX over cytosolic CAs. The crystal structures of two of these compounds in complex with a CA IX-mimic (a variant of CA II, with active site residues that mimic CA IX) and one compound in complex with CA II have been determined to 1.7 Å resolution or better and demonstrate a selective mechanism of binding between the hydrophilic and hydrophobic pockets of CA IX versus CA II. These compounds present promising candidates for anti-CA IX drugs and the treatment for several aggressive cancer types.

PubMed: 25254302
DOI: 10.1021/jm5012935

実験手法

X-RAY DIFFRACTION (1.64 Å)