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4Z87

Structure of the IMP dehydrogenase from Ashbya gossypii bound to GDP

Summary for 4Z87
Entry DOI10.2210/pdb4z87/pdb
DescriptorInosine-5'-monophosphate dehydrogenase, GUANOSINE-5'-MONOPHOSPHATE, GUANOSINE-5'-DIPHOSPHATE, ... (6 entities in total)
Functional Keywordsimp dehydrgoenase, bateman domain, oxidoreductase
Biological sourceAshbya gossypii (strain ATCC 10895)
Total number of polymer chains4
Total formula weight234398.66
Authors
Buey, R.M.,de Pereda, J.M.,Revuelta, J.L. (deposition date: 2015-04-08, release date: 2015-11-25, Last modification date: 2024-01-10)
Primary citationBuey, R.M.,Ledesma-Amaro, R.,Velazquez-Campoy, A.,Balsera, M.,Chagoyen, M.,de Pereda, J.M.,Revuelta, J.L.
Guanine nucleotide binding to the Bateman domain mediates the allosteric inhibition of eukaryotic IMP dehydrogenases.
Nat Commun, 6:8923-8923, 2015
Cited by
PubMed 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.
PubMed: 26558346
DOI: 10.1038/ncomms9923
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.25 Å)
Structure validation

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