7R0D

Structure of NUDT15 in complex with Geranyl monophosphate

これはPDB形式変換不可エントリーです。

7R0D の概要

• エントリーDOI: 10.2210/pdb7r0d/pdb
• 分子名称: Probable 8-oxo-dGTP diphosphatase NUDT15, Geranyl phosphate, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: nudt15, nudix, mth2, terpenes, hydrolase
• 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: 37787.07

構造登録者

Scaletti, E.R.,Stenmark, P. (登録日: 2022-02-01, 公開日: 2023-11-29, 最終更新日: 2024-09-04)

主引用文献

Scaletti, E.R.,Unterlass, J.E.,Almlof, I.,Koolmeister, T.,Vallin, K.S.,Kapsitidou, D.,Tsuber, V.,Helleday, T.,Stenmark, P.,Jemth, A.S.
Kinetic and structural characterization of NUDT15 and NUDT18 as catalysts of isoprene pyrophosphate hydrolysis.
Febs J., 2024

PubMed Abstract: Isoprene pyrophosphates play a crucial role in the synthesis of a diverse array of essential nonsterol and sterol biomolecules and serve as substrates for posttranslational isoprenylation of proteins, enabling specific anchoring to cellular membranes. Hydrolysis of isoprene pyrophosphates would be a means to modulate their levels, downstream products, and protein isoprenylation. While NUDIX hydrolases from plants have been described to catalyze the hydrolysis of isoprene pyrophosphates, homologous enzymes with this function in animals have not yet been reported. In this study, we screened an extensive panel of human NUDIX hydrolases for activity in hydrolyzing isoprene pyrophosphates. We found that human nucleotide triphosphate diphosphatase NUDT15 and 8-oxo-dGDP phosphatase NUDT18 efficiently catalyze the hydrolysis of several physiologically relevant isoprene pyrophosphates. Notably, we demonstrate that geranyl pyrophosphate is an excellent substrate for NUDT18, with a catalytic efficiency of 2.1 × 10 m·s, thus making it the best substrate identified for NUDT18 to date. Similarly, geranyl pyrophosphate proved to be the best isoprene pyrophosphate substrate for NUDT15, with a catalytic efficiency of 4.0 × 10 M·s. LC-MS analysis of NUDT15 and NUDT18 catalyzed isoprene pyrophosphate hydrolysis revealed the generation of the corresponding monophosphates and inorganic phosphate. Furthermore, we solved the crystal structure of NUDT15 in complex with the hydrolysis product geranyl phosphate at a resolution of 1.70 Å. This structure revealed that the active site nicely accommodates the hydrophobic isoprenoid moiety and helped identify key binding residues. Our findings imply that isoprene pyrophosphates are endogenous substrates of NUDT15 and NUDT18, suggesting they are involved in animal isoprene pyrophosphate metabolism.

PubMed: 38944687
DOI: 10.1111/febs.17202

実験手法

X-RAY DIFFRACTION (1.7 Å)