4ZWZ

Engineered Carbonic Anhydrase IX mimic in complex with a glucosyl sulfamate inhibitor

4ZWZ の概要

• エントリーDOI: 10.2210/pdb4zwz/pdb
• 関連するPDBエントリー: 4ZWX 4ZWY 4ZX0 4ZX1
• 分子名称: Carbonic anhydrase 2, ZINC ION, methyl (2S,4R)-1-[(2S,3R,4R,5S,6S)-6-(hydroxymethyl)-3,4,5-tris(oxidanyl)oxan-2-yl]sulfonyl-4-sulfamoyloxy-pyrrolidine-2-carbox ylate, ... (5 entities in total)
• 機能のキーワード: carbonic anhydrase ix mimic, glucosyl sulfamate, inhibitor complex., 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: 29516.58

構造登録者

Mahon, B.P.,Lomelino, C.L.,Driscoll, J.M.,McKenna, R. (登録日: 2015-05-19, 公開日: 2015-08-05, 最終更新日: 2023-09-27)

主引用文献

Mahon, B.P.,Lomelino, C.L.,Ladwig, J.,Rankin, G.M.,Driscoll, J.M.,Salguero, A.L.,Pinard, M.A.,Vullo, D.,Supuran, C.T.,Poulsen, S.A.,McKenna, R.
Mapping Selective Inhibition of the Cancer-Related Carbonic Anhydrase IX Using Structure-Activity Relationships of Glucosyl-Based Sulfamates.
J.Med.Chem., 58:6630-6638, 2015

PubMed Abstract: Inhibition of human carbonic anhydrase IX (hCA IX) has shown to be therapeutically advantageous for treating many types of highly aggressive cancers. However, designing selective inhibitors for hCA IX has been difficult due to its high structural homology and sequence similarity with off-target hCAs. Recently, the use of glucosyl sulfamate inhibitors has shown promise as selective inhibitors for hCA IX. In this study, we present five X-ray crystal structures, determined to a resolution of 1.7 Å or better, of both hCA II (a ubiquitous CA) and an engineered hCA IX-mimic in complex with selected glucosyl sulfamates and structurally rationalize mechanisms for hCA IX selectivity. Results from this study have allowed us, for the first time, to empirically "map" key interactions of the hCA IX active site in order to establish parameters needed to design novel hCA IX selective inhibitors.

PubMed: 26203869
DOI: 10.1021/acs.jmedchem.5b00845

実験手法

X-RAY DIFFRACTION (1.62 Å)