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8U7Q

Human retinal variant phosphomimetic IMPDH1(546)-S477D filament bound by GTP, ATP, IMP, and NAD+, octamer-centered

Summary for 8U7Q
Entry DOI10.2210/pdb8u7q/pdb
Related8U7M
EMDB information41989
DescriptorInosine-5'-monophosphate dehydrogenase 1, GUANOSINE-5'-TRIPHOSPHATE, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (5 entities in total)
Functional Keywordsdehydrogenase, nucleotide synthesis, filament, phosphomimetic, oxidoreductase
Biological sourceHomo sapiens (human)
Total number of polymer chains8
Total formula weight488864.62
Authors
Calise, S.J.,Kollman, J.M. (deposition date: 2023-09-15, release date: 2024-01-31, Last modification date: 2024-02-14)
Primary citationCalise, S.J.,O'Neill, A.G.,Burrell, A.L.,Dickinson, M.S.,Molfino, J.,Clarke, C.,Quispe, J.,Sokolov, D.,Buey, R.M.,Kollman, J.M.
Light-sensitive phosphorylation regulates retinal IMPDH1 activity and filament assembly.
J.Cell Biol., 223:-, 2024
Cited by
PubMed Abstract: Inosine monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme in guanosine triphosphate (GTP) synthesis and assembles into filaments in cells, which desensitizes the enzyme to feedback inhibition and boosts nucleotide production. The vertebrate retina expresses two splice variants IMPDH1(546) and IMPDH1(595). In bovine retinas, residue S477 is preferentially phosphorylated in the dark, but the effects on IMPDH1 activity and regulation are unclear. Here, we generated phosphomimetic mutants to investigate structural and functional consequences of S477 phosphorylation. The S477D mutation resensitized both variants to GTP inhibition but only blocked assembly of IMPDH1(595) filaments. Cryo-EM structures of both variants showed that S477D specifically blocks assembly of a high-activity assembly interface, still allowing assembly of low-activity IMPDH1(546) filaments. Finally, we discovered that S477D exerts a dominant-negative effect in cells, preventing endogenous IMPDH filament assembly. By modulating the structure and higher-order assembly of IMPDH, S477 phosphorylation acts as a mechanism for downregulating retinal GTP synthesis in the dark when nucleotide turnover is decreased.
PubMed: 38323936
DOI: 10.1083/jcb.202310139
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (3.3 Å)
Structure validation

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