6UC2

Human IMPDH2 treated with ATP and 2 mM GTP. Free canonical octamer reconstruction.

Summary for 6UC2

• Entry DOI: 10.2210/pdb6uc2/pdb
• EMDB information: 20725
• Descriptor: Inosine-5'-monophosphate dehydrogenase 2, GUANOSINE-5'-TRIPHOSPHATE, ADENOSINE-5'-TRIPHOSPHATE (3 entities in total)
• Functional Keywords: metabolism, filament, allostery, adenine, guanine, biosynthetic protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 8
• Total formula weight: 464272.33

Authors

Johnson, M.C.,Kollman, J.M. (deposition date: 2019-09-13, release date: 2020-03-25, Last modification date: 2025-05-21)

Primary citation

Johnson, M.C.,Kollman, J.M.
Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation.
Elife, 9:-, 2020

PubMed Abstract: 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.

PubMed: 31999252
DOI: 10.7554/eLife.53243

Experimental method

ELECTRON MICROSCOPY (4.48 Å)