7res | pdb_00007res
HUMAN IMPDH1 TREATED WITH ATP, IMP, AND NAD+, OCTAMER-CENTERED
Structural highlights
Disease[IMDH1_HUMAN] Defects in IMPDH1 are the cause of retinitis pigmentosa type 10 (RP10) [MIM:180105]. RP leads to degeneration of retinal photoreceptor cells. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. RP10 inheritance is autosomal dominant.[1] [2] [3] Defects in IMPDH1 are the cause of Leber congenital amaurosis type 11 (LCA11) [MIM:613837]. LCA11 is a severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia and keratoconus.[4] Function[IMDH1_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 PubMedInosine-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. 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 Nat Struct Mol Biol. 2022 Jan;29(1):47-58. doi: 10.1038/s41594-021-00706-2. Epub , 2022 Jan 10. PMID:35013599[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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