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6udo

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Human IMPDH2 treated with ATP, IMP, and 20 mM GTP. Fully compressed filament segment reconstruction.

Structural highlights

6udo is a 16 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.21Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

Inosine monophosphate dehydrogenase (IMPDH) mediates the first committed step in guanine nucleotide biosynthesis and plays important roles in cellular proliferation and the immune response. IMPDH reversibly polymerizes in cells and tissues in response to changes in metabolic demand. Self-assembly of metabolic enzymes is increasingly recognized as a general mechanism for regulating activity, typically by stabilizing specific conformations of an enzyme, but the regulatory role of IMPDH filaments has remained unclear. Here, we report a series of human IMPDH2 cryo-EM structures in both active and inactive conformations. The structures define the mechanism of filament assembly, and reveal how filament-dependent allosteric regulation of IMPDH2 makes the enzyme less sensitive to feedback inhibition, explaining why assembly occurs under physiological conditions that require expansion of guanine nucleotide pools. Tuning sensitivity to an allosteric inhibitor distinguishes IMPDH from other metabolic filaments, and highlights the diversity of regulatory outcomes that can emerge from self-assembly.

Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation.,Johnson MC, Kollman JM Elife. 2020 Jan 30;9. pii: 53243. doi: 10.7554/eLife.53243. PMID:31999252^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Johnson MC, Kollman JM. Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation. Elife. 2020 Jan 30;9. pii: 53243. doi: 10.7554/eLife.53243. PMID:31999252 doi:http://dx.doi.org/10.7554/eLife.53243