6QL3

Crystal structure of chimeric carbonic anhydrase VI with 3-(cyclooctylamino)-2,5,6-trifluoro-4-[(2-hydroxyethyl)sulfonyl]benzenesulfonamide

6QL3 の概要

• エントリーDOI: 10.2210/pdb6ql3/pdb
• 関連するPDBエントリー: 6QL1 6QL2
• 分子名称: Carbonic anhydrase 2, ZINC ION, 3-(cyclooctylamino)-2,5,6-trifluoro-4-[(2-hydroxyethyl)sulfonyl]benzenesulfonamide, ... (9 entities in total)
• 機能のキーワード: drug design, carbonic anhydrase, benzenesulfonamide, metal-binding, lyase-lyase inhibitor complex, 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: 30654.83

構造登録者

Smirnov, A.,Manakova, E.,Grazulis, S. (登録日: 2019-01-31, 公開日: 2019-09-25, 最終更新日: 2024-01-24)

主引用文献

Kazokaite, J.,Kairys, V.,Smirnoviene, J.,Smirnov, A.,Manakova, E.,Tolvanen, M.,Parkkila, S.,Matulis, D.
Engineered Carbonic Anhydrase VI-Mimic Enzyme Switched the Structure and Affinities of Inhibitors.
Sci Rep, 9:12710-12710, 2019

PubMed Abstract: Secretory human carbonic anhydrase VI (CA VI) has emerged as a potential drug target due to its role in pathological states, such as excess acidity-caused dental caries and injuries of gastric epithelium. Currently, there are no available CA VI-selective inhibitors or crystallographic structures of inhibitors bound to CA VI. The present study focuses on the site-directed CA II mutant mimicking the active site of CA VI for inhibitor screening. The interactions between CA VI-mimic and a series of benzenesulfonamides were evaluated by fluorescent thermal shift assay, stopped-flow CO hydration assay, isothermal titration calorimetry, and X-ray crystallography. Kinetic parameters showed that A65T, N67Q, F130Y, V134Q, L203T mutations did not influence catalytic properties of CA II, but inhibitor affinities resembled CA VI, exhibiting up to 0.16 nM intrinsic affinity for CA VI-mimic. Structurally, binding site of CA VI-mimic was found to be similar to CA VI. The ligand interactions with mutated side chains observed in three crystallographic structures allowed to rationalize observed variation of binding modes and experimental binding affinities to CA VI. This integrative set of kinetic, thermodynamic, and structural data revealed CA VI-mimic as a useful model to design CA VI-specific inhibitors which could be beneficial for novel therapeutic applications.

PubMed: 31481705
DOI: 10.1038/s41598-019-49094-0

実験手法

X-RAY DIFFRACTION (1.35 Å)