7ZEE

Human cytosolic 5' nucleotidase IIIB

7ZEE の概要

• エントリーDOI: 10.2210/pdb7zee/pdb
• 分子名称: 7-methylguanosine phosphate-specific 5'-nucleotidase, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: cytosolic 5' nucleotidase, n7 methylguanosine monophosphate dephosphorylation, mrna cap degradation, nucleotide level regulation, hydrolase
• 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: 35702.11

構造登録者

Kubacka, D.,Kozarski, M.,Baranowski, M.R.,Wojcik, R.,Jemielity, J.,Kowalska, J.,Basquin, J. (登録日: 2022-03-31, 公開日: 2022-04-13, 最終更新日: 2024-01-31)

主引用文献

Kubacka, D.,Kozarski, M.,Baranowski, M.R.,Wojcik, R.,Panecka-Hofman, J.,Strzelecka, D.,Basquin, J.,Jemielity, J.,Kowalska, J.
Substrate-Based Design of Cytosolic Nucleotidase IIIB Inhibitors and Structural Insights into Inhibition Mechanism.
Pharmaceuticals, 15:-, 2022

PubMed Abstract: Cytosolic nucleotidases (cNs) catalyze dephosphorylation of nucleoside 5'-monophosphates and thereby contribute to the regulation of nucleotide levels in cells. cNs have also been shown to dephosphorylate several therapeutically relevant nucleotide analogues. cN-IIIB has shown in vitro a distinctive activity towards 7-mehtylguanosine monophosphate (mGMP), which is one key metabolites of mRNA cap. Consequently, it has been proposed that cN-IIIB participates in mRNA cap turnover and prevents undesired accumulation and salvage of mGMP. Here, we sought to develop molecular tools enabling more advanced studies on the cellular role of cN-IIIB. To that end, we performed substrate and inhibitor property profiling using a library of 41 substrate analogs. The most potent hit compounds (identified among mGMP analogs) were used as a starting point for structure-activity relationship studies. As a result, we identified several 7-benzylguanosine 5'-monophosphate (BnGMP) derivatives as potent, unhydrolyzable cN-IIIB inhibitors. The mechanism of inhibition was elucidated using X-ray crystallography and molecular docking. Finally, we showed that compounds that potently inhibit recombinant cN-IIIB have the ability to inhibit mGMP decay in cell lysates.

PubMed: 35631380
DOI: 10.3390/ph15050554

実験手法

X-RAY DIFFRACTION (1.36 Å)