7RGI

HUMAN RETINAL VARIANT IMPDH1(546) TREATED WITH GTP, ATP, IMP, NAD+; INTERFACE-CENTERED

Summary for 7RGI

• Entry DOI: 10.2210/pdb7rgi/pdb
• EMDB information: 24450
• Descriptor: Inosine-5'-monophosphate dehydrogenase 1, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, INOSINIC ACID (3 entities in total)
• Functional Keywords: metabolism, filament, allostery, adenine, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 8
• Total formula weight: 475059.21

Authors

Burrell, A.L.,Kollman, J.M. (deposition date: 2021-07-15, release date: 2022-01-12, Last modification date: 2024-06-05)

Primary citation

Burrell, A.L.,Nie, C.,Said, M.,Simonet, J.C.,Fernandez-Justel, D.,Johnson, M.C.,Quispe, J.,Buey, R.M.,Peterson, J.R.,Kollman, J.M.
IMPDH1 retinal variants control filament architecture to tune allosteric regulation.
Nat.Struct.Mol.Biol., 29:47-58, 2022

PubMed Abstract: Inosine-5'-monophosphate dehydrogenase (IMPDH), a key regulatory enzyme in purine nucleotide biosynthesis, dynamically assembles filaments in response to changes in metabolic demand. Humans have two isoforms: IMPDH2 filaments reduce sensitivity to feedback inhibition, while IMPDH1 assembly remains uncharacterized. IMPDH1 plays a unique role in retinal metabolism, and point mutants cause blindness. Here, in a series of cryogenic-electron microscopy structures we show that human IMPDH1 assembles polymorphic filaments with different assembly interfaces in extended and compressed states. Retina-specific splice variants introduce structural elements that reduce sensitivity to GTP inhibition, including stabilization of the extended filament form. Finally, we show that IMPDH1 disease mutations fall into two classes: one disrupts GTP regulation and the other has no effect on GTP regulation or filament assembly. These findings provide a foundation for understanding the role of IMPDH1 in retinal function and disease and demonstrate the diverse mechanisms by which metabolic enzyme filaments are allosterically regulated.

PubMed: 35013599
DOI: 10.1038/s41594-021-00706-2

Experimental method

ELECTRON MICROSCOPY (3.6 Å)