7PP9

Three dimensional structure of human carbonic anhydrase XII in complex with sulfonamide

7PP9 の概要

• エントリーDOI: 10.2210/pdb7pp9/pdb
• 分子名称: Carbonic anhydrase 12, ZINC ION, methyl 2-chloranyl-4-cyclohexylsulfanyl-5-sulfamoyl-benzoate, ... (4 entities in total)
• 機能のキーワード: ca xii, ca 12, carbonic anhydrase xii, carbonic anhydrase 12, lyase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 121145.96

構造登録者

Leitans, J.,Tars, K.,Dvinskis, E. (登録日: 2021-09-13, 公開日: 2022-09-21, 最終更新日: 2024-10-16)

主引用文献

Zaksauskas, A.,Capkauskaite, E.,Paketuryte-Latve, V.,Smirnov, A.,Leitans, J.,Kazaks, A.,Dvinskis, E.,Stancaitis, L.,Mickeviciute, A.,Jachno, J.,Jezepcikas, L.,Linkuviene, V.,Sakalauskas, A.,Manakova, E.,Grazulis, S.,Matuliene, J.,Tars, K.,Matulis, D.
Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX.
Int J Mol Sci, 23:-, 2021

PubMed Abstract: Among the twelve catalytically active carbonic anhydrase isozymes present in the human body, the CAIX is highly overexpressed in various solid tumors. The enzyme acidifies the tumor microenvironment enabling invasion and metastatic processes. Therefore, many attempts have been made to design chemical compounds that would exhibit high affinity and selective binding to CAIX over the remaining eleven catalytically active CA isozymes to limit undesired side effects. It has been postulated that such drugs may have anticancer properties and could be used in tumor treatment. Here we have designed a series of compounds, methyl 5-sulfamoyl-benzoates, which bear a primary sulfonamide group, a well-known marker of CA inhibitors, and determined their affinities for all twelve CA isozymes. Variations of substituents on the benzenesulfonamide ring led to compound , which exhibited an extremely high binding affinity to CAIX; the was 0.12 nM. The dissociation constant, where the binding-linked protonation reactions have been subtracted, reached 0.08 pM. The compound also exhibited more than 100-fold selectivity over the remaining CA isozymes. The X-ray crystallographic structure of compound bound to CAIX showed the structural position, while several structures of compounds bound to other CA isozymes showed structural reasons for compound selectivity towards CAIX. Since this series of compounds possess physicochemical properties suitable for drugs, they may be developed for anticancer therapeutic purposes.

PubMed: 35008553
DOI: 10.3390/ijms23010130

実験手法

X-RAY DIFFRACTION (2.34 Å)