4Z0G

Structure of the IMPDH from Ashbya gossypii bound to GMP

Summary for 4Z0G

• Entry DOI: 10.2210/pdb4z0g/pdb
• Related: 4XWU
• Descriptor: Inosine-5'-monophosphate dehydrogenase,Inosine-5'-monophosphate dehydrogenase, GUANOSINE-5'-MONOPHOSPHATE, POTASSIUM ION, ... (5 entities in total)
• Functional Keywords: oxidoreductase
• Biological source: Ashbya gossypii (strain ATCC 10895 / CBS 109.51 / FGSC 9923 / NRRL Y-1056); More
• Total number of polymer chains: 2
• Total formula weight: 90772.38

Authors

Buey, R.M.,de Pereda, J.M.,Revuelta, J.L. (deposition date: 2015-03-26, release date: 2015-11-25, Last modification date: 2024-01-10)

Primary citation

Buey, 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

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

Experimental method

X-RAY DIFFRACTION (1.25 Å)