A nucleotide-controlled conformational switch modulates the activity of eukaryotic IMP dehydrogenases

Abstract Inosine-5′-monophosphate dehydrogenase (IMPDH) is an essential enzyme for nucleotide metabolism and cell proliferation. Despite IMPDH is the target of drugs with antiviral, immunosuppressive and antitumor activities, its physiological mechanisms of regulation remain largely unknown. Using t...

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Autores principales:	Rubén M. Buey, David Fernández-Justel, Íñigo Marcos-Alcalde, Graeme Winter, Paulino Gómez-Puertas, José María de Pereda, José Luis Revuelta
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e25f495f01384a6dbd80c2e6b87dba31
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spelling	oai:doaj.org-article:e25f495f01384a6dbd80c2e6b87dba312021-12-02T15:05:43ZA nucleotide-controlled conformational switch modulates the activity of eukaryotic IMP dehydrogenases10.1038/s41598-017-02805-x2045-2322https://doaj.org/article/e25f495f01384a6dbd80c2e6b87dba312017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02805-xhttps://doaj.org/toc/2045-2322Abstract Inosine-5′-monophosphate dehydrogenase (IMPDH) is an essential enzyme for nucleotide metabolism and cell proliferation. Despite IMPDH is the target of drugs with antiviral, immunosuppressive and antitumor activities, its physiological mechanisms of regulation remain largely unknown. Using the enzyme from the industrial fungus Ashbya gossypii, we demonstrate that the binding of adenine and guanine nucleotides to the canonical nucleotide binding sites of the regulatory Bateman domain induces different enzyme conformations with significantly distinct catalytic activities. Thereby, the comparison of their high-resolution structures defines the mechanistic and structural details of a nucleotide-controlled conformational switch that allosterically modulates the catalytic activity of eukaryotic IMPDHs. Remarkably, retinopathy-associated mutations lie within the mechanical hinges of the conformational change, highlighting its physiological relevance. Our results expand the mechanistic repertoire of Bateman domains and pave the road to new approaches targeting IMPDHs.Rubén M. BueyDavid Fernández-JustelÍñigo Marcos-AlcaldeGraeme WinterPaulino Gómez-PuertasJosé María de PeredaJosé Luis RevueltaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rubén M. Buey David Fernández-Justel Íñigo Marcos-Alcalde Graeme Winter Paulino Gómez-Puertas José María de Pereda José Luis Revuelta A nucleotide-controlled conformational switch modulates the activity of eukaryotic IMP dehydrogenases
description	Abstract Inosine-5′-monophosphate dehydrogenase (IMPDH) is an essential enzyme for nucleotide metabolism and cell proliferation. Despite IMPDH is the target of drugs with antiviral, immunosuppressive and antitumor activities, its physiological mechanisms of regulation remain largely unknown. Using the enzyme from the industrial fungus Ashbya gossypii, we demonstrate that the binding of adenine and guanine nucleotides to the canonical nucleotide binding sites of the regulatory Bateman domain induces different enzyme conformations with significantly distinct catalytic activities. Thereby, the comparison of their high-resolution structures defines the mechanistic and structural details of a nucleotide-controlled conformational switch that allosterically modulates the catalytic activity of eukaryotic IMPDHs. Remarkably, retinopathy-associated mutations lie within the mechanical hinges of the conformational change, highlighting its physiological relevance. Our results expand the mechanistic repertoire of Bateman domains and pave the road to new approaches targeting IMPDHs.
format	article
author	Rubén M. Buey David Fernández-Justel Íñigo Marcos-Alcalde Graeme Winter Paulino Gómez-Puertas José María de Pereda José Luis Revuelta
author_facet	Rubén M. Buey David Fernández-Justel Íñigo Marcos-Alcalde Graeme Winter Paulino Gómez-Puertas José María de Pereda José Luis Revuelta
author_sort	Rubén M. Buey
title	A nucleotide-controlled conformational switch modulates the activity of eukaryotic IMP dehydrogenases
title_short	A nucleotide-controlled conformational switch modulates the activity of eukaryotic IMP dehydrogenases
title_full	A nucleotide-controlled conformational switch modulates the activity of eukaryotic IMP dehydrogenases
title_fullStr	A nucleotide-controlled conformational switch modulates the activity of eukaryotic IMP dehydrogenases
title_full_unstemmed	A nucleotide-controlled conformational switch modulates the activity of eukaryotic IMP dehydrogenases
title_sort	nucleotide-controlled conformational switch modulates the activity of eukaryotic imp dehydrogenases
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e25f495f01384a6dbd80c2e6b87dba31
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A nucleotide-controlled conformational switch modulates the activity of eukaryotic IMP dehydrogenases

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