6RPU
Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP
Summary for 6RPU
| Entry DOI | 10.2210/pdb6rpu/pdb |
| Descriptor | Inosine-5'-monophosphate dehydrogenase, P1-(5'-ADENOSYL)-P5-(5'-GUANOSYL) PENTAPHOSPHATE, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total) |
| Functional Keywords | imp dehydrogenase, bateman domain, dinucleoside polyphosphate, oxidoreductase |
| Biological source | Eremothecium gossypii ATCC 10895 |
| Total number of polymer chains | 1 |
| Total formula weight | 58138.18 |
| Authors | Buey, R.M.,Fernandez-Justel, D.,Revuelta, J.L. (deposition date: 2019-05-14, release date: 2019-08-28, Last modification date: 2024-01-24) |
| Primary citation | Fernandez-Justel, D.,Pelaez, R.,Revuelta, J.L.,Buey, R.M. The Bateman domain of IMP dehydrogenase is a binding target for dinucleoside polyphosphates. J.Biol.Chem., 294:14768-14775, 2019 Cited by PubMed Abstract: IMP dehydrogenase (IMPDH) is an essential enzyme that catalyzes the rate-limiting step in the guanine nucleotide biosynthetic pathway. Because of its involvement in the control of cell division and proliferation, IMPDH represents a therapeutic for managing several diseases, including microbial infections and cancer. IMPDH must be tightly regulated, but the molecular mechanisms responsible for its physiological regulation remain unknown. To this end, we recently reported an important role of adenine and guanine mononucleotides that bind to the regulatory Bateman domain to allosterically modulate the catalytic activity of eukaryotic IMPDHs. Here, we have used enzyme kinetics, X-ray crystallography, and small-angle X-ray scattering (SAXS) methodologies to demonstrate that adenine/guanine dinucleoside polyphosphates bind to the Bateman domain of IMPDH from the fungus with submicromolar affinities. We found that these dinucleoside polyphosphates modulate the catalytic activity of IMPDHs by efficiently competing with the adenine/guanine mononucleotides for the allosteric sites. These results suggest that dinucleoside polyphosphates play important physiological roles in the allosteric regulation of IMPDHs by adding an additional mechanism for fine-tuning the activities of these enzymes. We propose that these findings may have important implications for the design of therapeutic strategies to inhibit IMPDHs. PubMed: 31416831DOI: 10.1074/jbc.AC119.010055 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.11 Å) |
Structure validation
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