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

Buey, R.M. ; Ledesma-Amaro, R. ; Velázquez-Campoy, A. (Universidad de Zaragoza) ; Balsera, M. ; Chagoyen, M. ; De Pereda, J.M. ; Revuelta, J.L.

Resumen: 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.

Idioma: Inglés

DOI: 10.1038/ncomms9923

Año: 2015

Publicado en: Nature Communications 6 (2015), 8923[11 pp]
ISSN: 2041-1723

Factor impacto JCR: 11.329 (2015)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 3 / 62 = 0.048 (2015) - Q1 - T1

Factor impacto SCIMAGO: 6.287 - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1) - Physics and Astronomy (miscellaneous) (Q1) - Chemistry (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/EC/FP7/293831/EU/Modulating EB protein interactions through small molecules/EB-SxIP
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2013-47064-P

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)