6i0m
From Proteopedia
Structure of human IMP dehydrogenase, isoform 2, bound to GDP
Structural highlights
Function[IMDH2_HUMAN] Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth. Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism. It may also have a role in the development of malignancy and the growth progression of some tumors.[HAMAP-Rule:MF_03156] Publication Abstract from PubMedIMP dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo GTP biosynthetic pathway and plays essential roles in cell proliferation. As a clinical target, IMPDH has been studied for decades but it has only been within the last years that we are starting to understand the complexity of the mechanisms of its physiological regulation. Here, we report structural and functional insights into how adenine and guanine nucleotides control a conformational switch that modulates the assembly of the two human IMPDH enzymes into cytoophidia and allosterically regulates their catalytic activity. In vitro reconstituted micron-length cytoophidia-like structures show catalytic activity comparable to unassembled IMPDH but, in turn, are more resistant to GTP/GDP allosteric inhibition. Therefore, IMPDH cytoophidia formation facilitates the accumulation of high levels of guanine nucleotides when the cell requires it. Finally, we demonstrate that most of the IMPDH retinopathy-associated mutations abrogate GTP/GDP-induced allosteric inhibition and alter cytoophidia dynamics. A Nucleotide-Dependent Conformational Switch Controls the Polymerization of Human IMP Dehydrogenases to Modulate their Catalytic Activity.,Fernandez-Justel D, Nunez R, Martin-Benito J, Jimeno D, Gonzalez-Lopez A, Soriano EM, Revuelta JL, Buey RM J Mol Biol. 2019 Jan 18. pii: S0022-2836(19)30029-4. doi:, 10.1016/j.jmb.2019.01.020. PMID:30664871[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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