4QIZ

Crystal structure of human carbonic anhydrase isozyme XIII with inhibitor

4QIZ の概要

• エントリーDOI: 10.2210/pdb4qiz/pdb
• 関連するPDBエントリー: 4QIY 4QJ0 4QJM 4QJO 4QJP 4QJW 4QJX 4QTL
• 分子名称: Carbonic anhydrase 13, ZINC ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: drug design, carbonic anhydrase, benzenesulfonamide, metal-binding, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 60604.73

構造登録者

Manakova, E.,Smirnov, A.,Grazulis, S. (登録日: 2014-06-03, 公開日: 2015-04-15, 最終更新日: 2023-11-08)

主引用文献

Dudutiene, V.,Zubriene, A.,Smirnov, A.,Timm, D.D.,Smirnoviene, J.,Kazokaite, J.,Michailoviene, V.,Zaksauskas, A.,Manakova, E.,Grazulis, S.,Matulis, D.
Functionalization of Fluorinated Benzenesulfonamides and Their Inhibitory Properties toward Carbonic Anhydrases
Chemmedchem, 10:662-687, 2015

PubMed Abstract: Substituted tri- and tetrafluorobenzenesulfonamides were designed, synthesized, and evaluated as high-affinity and isoform-selective carbonic anhydrase (CA) inhibitors. Their binding affinities for recombinant human CA I, II, VA, VI, VII, XII, and XIII catalytic domains were determined by fluorescent thermal shift assay, isothermal titration calorimetry, and a stopped-flow CO2 hydration assay. Variation of the substituents at the 2-, 3-, and 4-positions yielded compounds with a broad range of binding affinities and isoform selectivities. Several 2,4-substituted-3,5,6-trifluorobenzenesulfonamides were effective CA XIII inhibitors with high selectivity over off-target CA I and CA II. 3,4-Disubstituted-2,5,6-trifluorobenzenesulfonamides bound CAs with higher affinity than 2,4-disubstituted-3,5,6-trifluorobenzenesulfonamides. Many such fluorinated benzenesulfonamides were found to be nanomolar inhibitors of CA II, CA VII, tumor-associated CA IX and CA XII, and CA XIII. X-ray crystal structures of inhibitors bound in the active sites of several CA isoforms provide structure-activity relationship information for inhibitor binding affinities and selectivity.

PubMed: 25758852
DOI: 10.1002/cmdc.201402490

実験手法

X-RAY DIFFRACTION (1.55 Å)