8FUZ

Human IMPDH2 mutant - L245P, treated with GTP, ATP, IMP, and NAD+; filament assembly interface reconstruction

Summary for 8FUZ

• Entry DOI: 10.2210/pdb8fuz/pdb
• EMDB information: 29357 29482
• Descriptor: Inosine-5'-monophosphate dehydrogenase 2, INOSINIC ACID, NICOTINAMIDE-ADENINE-DINUCLEOTIDE (3 entities in total)
• Functional Keywords: filament, dehydrogenase, cbs domain, bateman domain, purine biosynthesis, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 8
• Total formula weight: 459808.67

Authors

O'Neill, A.G.,Kollman, J.M. (deposition date: 2023-01-18, release date: 2023-04-19, Last modification date: 2024-11-06)

Primary citation

O'Neill, A.G.,Burrell, A.L.,Zech, M.,Elpeleg, O.,Harel, T.,Edvardson, S.,Mor-Shaked, H.,Rippert, A.L.,Nomakuchi, T.,Izumi, K.,Kollman, J.M.
Neurodevelopmental disorder mutations in the purine biosynthetic enzyme IMPDH2 disrupt its allosteric regulation.
J.Biol.Chem., 299:105012-105012, 2023

PubMed Abstract: 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.

PubMed: 37414152
DOI: 10.1016/j.jbc.2023.105012

Experimental method

ELECTRON MICROSCOPY (2.1 Å)