8g8f

From Proteopedia

Human IMPDH2 mutant - L245P, treated with ATP, IMP, and NAD+; extended filament segment reconstruction

Structural highlights

8g8f is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.6Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

IMDH2_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 PubMed

Inosine 5' monophosphate dehydrogenase (IMPDH) is a critical regulatory enzyme in purine nucleotide biosynthesis that is inhibited by the downstream product GTP. Multiple point mutations in the human isoform IMPDH2 have recently been associated with dystonia and other neurodevelopmental disorders, but the effect of the mutations on enzyme function has not been described. Here, we report the identification of two additional missense variants in IMPDH2 from affected individuals and show that all of the disease-associated mutations disrupt GTP regulation. Cryo-EM structures of one IMPDH2 mutant suggest this regulatory defect arises from a shift in the conformational equilibrium toward a more active state. This structural and functional analysis provides insight into IMPDH2-associated disease mechanisms that point to potential therapeutic approaches and raises new questions about fundamental aspects of IMPDH regulation.

Neurodevelopmental disorder mutations in the purine biosynthetic enzyme IMPDH2 disrupt its allosteric regulation.,O'Neill AG, Burrell AL, Zech M, Elpeleg O, Harel T, Edvardson S, Mor-Shaked H, Rippert AL, Nomakuchi T, Izumi K, Kollman JM J Biol Chem. 2023 Aug;299(8):105012. doi: 10.1016/j.jbc.2023.105012. Epub 2023 , Jul 4. PMID:37414152^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ O'Neill AG, Burrell AL, Zech M, Elpeleg O, Harel T, Edvardson S, Mor-Shaked H, Rippert AL, Nomakuchi T, Izumi K, Kollman JM. Neurodevelopmental disorder mutations in the purine biosynthetic enzyme IMPDH2 disrupt its allosteric regulation. J Biol Chem. 2023 Aug;299(8):105012. PMID:37414152 doi:10.1016/j.jbc.2023.105012