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The Bateman domain of IMP dehydrogenase is a binding target for dinucleoside polyphosphates

DOI: 10.1074/jbc.AC119.010055 DOI Help

Authors: David Fernandez-justel (University of Salamanca) , Rafael Peláez (University of Salamanca) , José Luis Revuelta (University of Salamanca) , Ruben M. Buey (University of Salamanca)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry

State: Published (Approved)
Published: August 2019
Diamond Proposal Number(s): 8311

Abstract: IMP dehydrogenase (IMPDH) is an essential enzyme that catalyzes the rate-limiting step in the de novo 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 Xray scattering (SAXS) methodologies to demonstrate that adenine/guanine dinucleoside polyphosphates bind to the Bateman domain of IMPDH from the fungus Ashbya gossypii with submicromolar affinities. We found that these dinucleoside polyphosphates modulate the catalytic activity of IMPDHs in vitro 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.

Journal Keywords: IMP dehydrogenase; dinucleoside polyphosphates; Bateman domain; conformational switch; molecular sensor; structural biology; allosteric regulation; conformational change; X-ray crystallography; small-angle X-ray scattering (SAXS)

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: B21-High Throughput SAXS