Investigating Active Site Binding of Ligands to High and Low Activity Carbonic Anhydrase Enzymes Using Native Mass Spectrometry,Journal of Medicinal Chemistry

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Investigating Active Site Binding of Ligands to High and Low Activity Carbonic Anhydrase Enzymes Using Native Mass Spectrometry
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-20 , DOI: 10.1021/acs.jmedchem.4c01512
Yezhou Yu _{1,

2} , Louise M Sternicki ₁ , David H Hilko ₁ , Russell J Jarrott ₂ , Giovanna Di Trapani ₂ , Kathryn F Tonissen _{1,

2} , Sally-Ann Poulsen _{1,

2}

Affiliation

Carbonic anhydrases (CAs) are a family of enzymes that play an important pH regulatory role in health and disease. While different CA isozymes have a high degree of structural similarity, they have variable enzymatic activity, with CA III being the least active and having less than 1% of the activity of CA II, the most active. Furthermore, ligand binding studies for CA III are limited, and a resulting lack of chemical probes impedes understanding of this CA isozyme in comparison to other CA family members where studies are abundant. Therefore, we employed native mass spectrometry (nMS), also known as intact mass spectrometry, to assess ligand binding to CA II and CA III and discovered two novel compounds that for the first time display strong binding to CA III. We present a new data visualization and quantification tool developed to display native mass spectra as an intuitive stacked heat map representation for rapidly interpreting the results of ligand-protein binding from nMS screening.

中文翻译：

使用天然质谱研究配体与高活性和低活性碳酸酐酶的活性位点结合

碳酸酐酶 (CA) 是一类酶，在健康和疾病中发挥着重要的 pH 调节作用。虽然不同的CA同工酶具有高度的结构相似性，但它们具有不同的酶活性，其中CA III的活性最低，其活性不到CA II（最活跃）的1%。此外，CA III 的配体结合研究是有限的，并且与研究丰富的其他 CA 家族成员相比，化学探针的缺乏阻碍了对该 CA 同工酶的理解。因此，我们采用天然质谱 (nMS)（也称为完整质谱）来评估配体与 CA II 和 CA III 的结合，并发现了两种首次显示与 CA III 强结合的新化合物。我们提出了一种新的数据可视化和量化工具，用于将天然质谱显示为直观的堆叠热图表示，以便快速解释 nMS 筛选的配体-蛋白质结合结果。

更新日期：2024-08-20

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