7AES

Human carbonic anhydrase II in complex with 2,3,5,6-tetrafluoro-N-methyl-4-propylsulfanyl-benzenesulfonamide

7AES の概要

• エントリーDOI: 10.2210/pdb7aes/pdb
• 分子名称: carbonic anhydrase 2, ZINC ION, 2,3,5,6-tetrakis(fluoranyl)-~{N}-methyl-4-propylsulfanyl-benzenesulfonamide, ... (7 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
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 30076.18

構造登録者

Paketuryte, V.,Smirnov, A.,Manakova, E.,Grazulis, S. (登録日: 2020-09-18, 公開日: 2021-09-01, 最終更新日: 2024-01-31)

主引用文献

Baronas, D.,Dudutiene, V.,Paketuryte, V.,Kairys, V.,Smirnov, A.,Juozapaitiene, V.,Vaskevicius, A.,Manakova, E.,Grazulis, S.,Zubriene, A.,Matulis, D.
Structure and mechanism of secondary sulfonamide binding to carbonic anhydrases.
Eur.Biophys.J., 50:993-1011, 2021

PubMed Abstract: Zinc-containing metalloenzyme carbonic anhydrase (CA) binds primary sulfonamides with extremely high, up to picomolar, affinity by forming a coordination bond between the negatively charged amino group and the zinc ion and making hydrogen bonds and hydrophobic contacts with other parts of the inhibitor molecule. However, N-methyl-substituted, secondary or tertiary sulfonamides bind CA with much lower affinity. In search for an explanation for this diminished affinity, a series of secondary sulfonamides were synthesized and, together with analogous primary sulfonamides, the affinities for 12 recombinant catalytically active human CA isoforms were determined by the fluorescent thermal shift assay, stopped-flow assay of the inhibition of enzymatic activity and isothermal titration calorimetry. The binding profile of secondary sulfonamides as a function of pH showed the same U-shape dependence seen for primary sulfonamides. This dependence demonstrated that there were protein binding-linked protonation reactions that should be dissected for the estimation of the intrinsic binding constants to perform structure-thermodynamics analysis. X-ray crystallographic structures of secondary sulfonamides and computational modeling dissected the atomic contributions to the binding energetics. Secondary sulfonamides bind to carbonic anhydrases via coordination bond between the negatively charged nitrogen of alkylated amino group and Zn(II) in the active site of CA. The binding reaction is linked to deprotonation of the amino group and protonation of the Zn(II)-bound hydroxide. To perform the structure-thermodynamics analysis, contributions of these linked reactions must be subtracted to determine the intrinsic energetics. In this aspect, the secondary sulfonamides are similar to primary sulfonamides as CA inhibitors.

PubMed: 34328515
DOI: 10.1007/s00249-021-01561-1

実験手法

X-RAY DIFFRACTION (1.4 Å)