Guanine nucleotide binding to the Bateman domain mediates the allosteric inhibition of eukaryotic IMP dehydrogenases

Rubén M. Buey (), Rodrigo Ledesma-Amaro, Adrián Velázquez-Campoy, Mónica Balsera, Mónica Chagoyen, José M. de Pereda and José L. Revuelta ()
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Rubén M. Buey: Metabolic Engineering Group, Dpto. Microbiología y Genética. Universidad de Salamanca, Campus Miguel de Unamuno, Edificio Departamental, Salamanca 37007, Spain
Rodrigo Ledesma-Amaro: Metabolic Engineering Group, Dpto. Microbiología y Genética. Universidad de Salamanca, Campus Miguel de Unamuno, Edificio Departamental, Salamanca 37007, Spain
Adrián Velázquez-Campoy: Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Unit IQFR-CSIC-BIFI, Universidad de Zaragoza, C/Mariano Esquillor, Zaragoza 50018, Spain
Mónica Balsera: Instituto de Recursos Naturales y Agrobiología (IRNASA-CSIC)
Mónica Chagoyen: Computational Systems Biology Group, Centro Nacional de Biotecnología (CNB-CSIC)
José M. de Pereda: Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Campus Miguel de Unamuno, Salamanca 37007, Spain
José L. Revuelta: Metabolic Engineering Group, Dpto. Microbiología y Genética. Universidad de Salamanca, Campus Miguel de Unamuno, Edificio Departamental, Salamanca 37007, Spain

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract Inosine-5′-monophosphate dehydrogenase (IMPDH) plays key roles in purine nucleotide metabolism and cell proliferation. Although IMPDH is a widely studied therapeutic target, there is limited information about its physiological regulation. Using Ashbya gossypii as a model, we describe the molecular mechanism and the structural basis for the allosteric regulation of IMPDH by guanine nucleotides. We report that GTP and GDP bind to the regulatory Bateman domain, inducing octamers with compromised catalytic activity. Our data suggest that eukaryotic and prokaryotic IMPDHs might have developed different regulatory mechanisms, with GTP/GDP inhibiting only eukaryotic IMPDHs. Interestingly, mutations associated with human retinopathies map into the guanine nucleotide-binding sites including a previously undescribed non-canonical site and disrupt allosteric inhibition. Together, our results shed light on the mechanisms of the allosteric regulation of enzymes mediated by Bateman domains and provide a molecular basis for certain retinopathies, opening the door to new therapeutic approaches.

Date: 2015
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DOI: 10.1038/ncomms9923

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