title: Guanine nucleotide binding to the Bateman domain mediates the allosteric inhibition of eukaryotic IMP dehydrogenases.
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.
authors.affiliation: Metabolic Engineering Group, Dpto. Microbiología y Genética. Universidad de Salamanca, Campus Miguel de Unamuno, Edificio Departamental, Salamanca 37007, Spain.
authors.forename: Rubén M
authors.initials: RM
authors.lastname: Buey
authors.affiliation: Metabolic Engineering Group, Dpto. Microbiología y Genética. Universidad de Salamanca, Campus Miguel de Unamuno, Edificio Departamental, Salamanca 37007, Spain.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Ledesma-Amaro
authors.affiliation: Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Unit IQFR-CSIC-BIFI, Universidad de Zaragoza, C/Mariano Esquillor, Zaragoza 50018, Spain.|Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, Zaragoza 50009, Spain.|Instituto de Investigaciones Sanitarias de Aragón (IIS-A), Zaragoza 50009, Spain.|Fundación ARAID, Government of Aragón, Zaragoza 50018, Spain.
authors.forename: Adrián
authors.initials: A
authors.lastname: Velázquez-Campoy
authors.affiliation: Department Abiotic Stress, Instituto de Recursos Naturales y Agrobiología (IRNASA-CSIC), Cordel de Merinas 40-52, Salamanca 37008, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Balsera
authors.affiliation: Computational Systems Biology Group, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, Madrid 28049, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Chagoyen
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Campus Miguel de Unamuno, Salamanca 37007, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: de Pereda
authors.affiliation: Metabolic Engineering Group, Dpto. Microbiología y Genética. Universidad de Salamanca, Campus Miguel de Unamuno, Edificio Departamental, Salamanca 37007, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Revuelta
mesh_terms: D000595:Amino Acid Sequence; D001203:Ascomycota / Q000201:enzymology* / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism*; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
chemical_list: D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase