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Article

Insight into the Binding and Hydrolytic Preferences of hNudt16 Based on Nucleotide Diphosphate Substrates

1
Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Pasteura 5, 02-093 Warsaw, Poland
2
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland
3
Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, Poland
4
Department of Macromolecular Physics, Faculty of Physics, Adam Mickiewicz University, Uniwersytetu Poznanskiego 2, 61-614 Poznan, Poland
5
National Synchrotron Radiation Centre SOLARIS, Jagiellonian University, Czerwone Maki 98, 30-392 Krakow, Poland
*
Author to whom correspondence should be addressed.
Academic Editor: Christophe Morisseau
Int. J. Mol. Sci. 2021, 22(20), 10929; https://doi.org/10.3390/ijms222010929
Received: 26 August 2021 / Revised: 28 September 2021 / Accepted: 5 October 2021 / Published: 10 October 2021
(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism)
Nudt16 is a member of the NUDIX family of hydrolases that show specificity towards substrates consisting of a nucleoside diphosphate linked to another moiety X. Several substrates for hNudt16 and various possible biological functions have been reported. However, some of these reports contradict each other and studies comparing the substrate specificity of the hNudt16 protein are limited. Therefore, we quantitatively compared the affinity of hNudt16 towards a set of previously published substrates, as well as identified novel potential substrates. Here, we show that hNudt16 has the highest affinity towards IDP and GppG, with Kd below 100 nM. Other tested ligands exhibited a weaker affinity of several orders of magnitude. Among the investigated compounds, only IDP, GppG, m7GppG, AppA, dpCoA, and NADH were hydrolyzed by hNudt16 with a strong substrate preference for inosine or guanosine containing compounds. A new identified substrate for hNudt16, GppG, which binds the enzyme with an affinity comparable to that of IDP, suggests another potential regulatory role of this protein. Molecular docking of hNudt16-ligand binding inside the hNudt16 pocket revealed two binding modes for representative substrates. Nucleobase stabilization by Π stacking interactions with His24 has been associated with strong binding of hNudt16 substrates. View Full-Text
Keywords: hNudt16; nudix family; dinucleoside diphosphates; GppG; IDP; MST; DSF; SAXS hNudt16; nudix family; dinucleoside diphosphates; GppG; IDP; MST; DSF; SAXS
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MDPI and ACS Style

Chrabąszczewska, M.; Winiewska-Szajewska, M.; Ostrowska, N.; Bojarska, E.; Stępiński, J.; Mancewicz, Ł.; Łukaszewicz, M.; Trylska, J.; Taube, M.; Kozak, M.; Darżynkiewicz, E.; Grzela, R. Insight into the Binding and Hydrolytic Preferences of hNudt16 Based on Nucleotide Diphosphate Substrates. Int. J. Mol. Sci. 2021, 22, 10929. https://doi.org/10.3390/ijms222010929

AMA Style

Chrabąszczewska M, Winiewska-Szajewska M, Ostrowska N, Bojarska E, Stępiński J, Mancewicz Ł, Łukaszewicz M, Trylska J, Taube M, Kozak M, Darżynkiewicz E, Grzela R. Insight into the Binding and Hydrolytic Preferences of hNudt16 Based on Nucleotide Diphosphate Substrates. International Journal of Molecular Sciences. 2021; 22(20):10929. https://doi.org/10.3390/ijms222010929

Chicago/Turabian Style

Chrabąszczewska, Magdalena, Maria Winiewska-Szajewska, Natalia Ostrowska, Elżbieta Bojarska, Janusz Stępiński, Łukasz Mancewicz, Maciej Łukaszewicz, Joanna Trylska, Michał Taube, Maciej Kozak, Edward Darżynkiewicz, and Renata Grzela. 2021. "Insight into the Binding and Hydrolytic Preferences of hNudt16 Based on Nucleotide Diphosphate Substrates" International Journal of Molecular Sciences 22, no. 20: 10929. https://doi.org/10.3390/ijms222010929

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