5JN9

Crystal structure for the complex of human carbonic anhydrase IV and ethoxyzolamide

5JN9 の概要

• エントリーDOI: 10.2210/pdb5jn9/pdb
• 関連するPDBエントリー: 5JN8 5JNA 5JNC 5JND
• 分子名称: Carbonic anhydrase 4, ZINC ION, 6-ethoxy-1,3-benzothiazole-2-sulfonamide, ... (7 entities in total)
• 機能のキーワード: carbonic anhydrase, lyase, inhibitor 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: 4
• 化学式量合計: 124007.76

構造登録者

Chen, Z.,Waheed, A.,Di Cera, E.,Sly, W.S. (登録日: 2016-04-29, 公開日: 2017-05-03, 最終更新日: 2023-09-27)

主引用文献

Mickeviciute, A.,Timm, D.D.,Gedgaudas, M.,Linkuviene, V.,Chen, Z.,Waheed, A.,Michailoviene, V.,Zubriene, A.,Smirnov, A.,Capkauskaite, E.,Baranauskiene, L.,Jachno, J.,Revuckiene, J.,Manakova, E.,Grazulis, S.,Matuliene, J.,Di Cera, E.,Sly, W.S.,Matulis, D.
Intrinsic thermodynamics of high affinity inhibitor binding to recombinant human carbonic anhydrase IV.
Eur. Biophys. J., 47:271-290, 2018

PubMed Abstract: Membrane-associated carbonic anhydrase (CA) isoform IV participates in carbon metabolism and pH homeostasis and is implicated in the development of eye diseases such as retinitis pigmentosa and glaucoma. A series of substituted benzenesulfonamides were designed and their binding affinity to CA IV was determined by fluorescent thermal shift assay and isothermal titration calorimetry (ITC). Compound [(4-chloro-2-phenylsulfanyl-5-sulfamoyl-benzoyl)amino]propyl acetate (19) bound CA IV with the K of 1.0 nM and exhibited significant selectivity over the remaining 11 human CA isoforms. The compound could be developed as a drug targeting CA IV. Various forms of recombinant CA IV were produced in Escherichia coli and mammalian cell cultures. Comparison of their temperature stability in various buffers and salt solutions demonstrated that CA IV is most stable at slightly alkaline conditions and at elevated sodium sulfate concentrations. High-resolution X-ray crystallographic structures of ortho-Cl and meta-thiazole-substituted benzene sulfonamide in complex with CA IV revealed the position of and interactions between the ligand and the protein. Sulfonamide inhibitor binding to CA IV is linked to several reactions-the deprotonation of the sulfonamide amino group, the protonation of CA-Zn(II)-bound hydroxide at the active site of CA IV, and the compensating reactions of the buffer. The dissection of binding-linked reactions yielded the intrinsic thermodynamic parameters, characterizing the interaction between CA IV and the sulfonamides in the binding-able protonation forms, including Gibbs energy, enthalpy, and entropy, that could be used for the characterization of binding to any CA in the process of drug design.

PubMed: 28975383
DOI: 10.1007/s00249-017-1256-0

実験手法

X-RAY DIFFRACTION (2.1 Å)