EMD-24442
HUMAN RETINAL VARIANT IMPDH1(595) TREATED WITH ATP, OCTAMER-CENTERED
EMD-24442
Single-particle3.7 Å
Deposition: 14/07/2021Map released: 12/01/2022
Last modified: 05/06/2024
Sample Organism:
Homo sapiens
Sample: Assembly interface of IMPDH1 filament bound to ATP, IMP, NAD+
Fitted models: 7rfh (Avg. Q-score: 0.475)
Deposition Authors: Burrell AL, Kollman JM
Sample: Assembly interface of IMPDH1 filament bound to ATP, IMP, NAD+
Fitted models: 7rfh (Avg. Q-score: 0.475)
Deposition Authors: Burrell AL, Kollman JM
IMPDH1 retinal variants control filament architecture to tune allosteric regulation.
Burrell AL,
Nie C,
Said M ,
Simonet JC,
Fernandez-Justel D ,
Johnson MC ,
Quispe J,
Buey RM ,
Peterson JR ,
Kollman JM
(2022) Nat Struct Mol Biol , 29 , 47 - 58
,
Simonet JC,
Fernandez-Justel D ,
Johnson MC ,
Quispe J,
Buey RM ,
Peterson JR ,
Kollman JM
(2022) Nat Struct Mol Biol , 29 , 47 - 58
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.
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.