EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Neurodevelopmental disorder mutations in the purine biosynthetic enzyme IMPDH2 disrupt its allosteric regulation.
ジャーナル・号・ページ	J Biol Chem, Vol. 299, Issue 8, Page 105012, Year 2023
掲載日	2023年7月4日
著者	Audrey G O'Neill / Anika L Burrell / Michael Zech / Orly Elpeleg / Tamar Harel / Simon Edvardson / Hagar Mor-Shaked / Alyssa L Rippert / Tomoki Nomakuchi / Kosuke Izumi / Justin M Kollman /
PubMed 要旨	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 ...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.
リンク	J Biol Chem / PubMed:37414152 / PubMed Central
手法	EM (単粒子)
解像度	2.0 - 3.0 Å
構造データ	29357 8foz EMDB-29357, PDB-8foz: Human IMPDH2 mutant - L245P, treated with ATP, IMP, and NAD+; filament assembly interface reconstruction 手法: EM (単粒子) / 解像度: 2.0 Å 29482 8fuz EMDB-29482, PDB-8fuz: Human IMPDH2 mutant - L245P, treated with GTP, ATP, IMP, and NAD+; filament assembly interface reconstruction 手法: EM (単粒子) / 解像度: 2.1 Å 29848 8g8f EMDB-29848, PDB-8g8f: Human IMPDH2 mutant - L245P, treated with ATP, IMP, and NAD+; extended filament segment reconstruction 手法: EM (単粒子) / 解像度: 2.6 Å 29863 8g9b EMDB-29863, PDB-8g9b: Human IMPDH2 mutant - L245P, treated with GTP, ATP, IMP, and NAD+; compressed filament segment reconstruction 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-29870: Human IMPDH2 mutant - L245P, treated with GTP, ATP, IMP, and NAD+; bent filament segment reconstruction 手法: EM (単粒子) / 解像度: 2.7 Å
化合物	ChemComp-IMP: INOSINIC ACID / IMP ChemComp-NAD: NICOTINAMIDE-ADENINE-DINUCLEOTIDE / NADYM ChemComp-ATP: ADENOSINE-5'-TRIPHOSPHATE / ATP / ATP, エネルギー貯蔵分子YM ChemComp-GTP: GUANOSINE-5'-TRIPHOSPHATE / GTP / GTP, エネルギー貯蔵分子*YM
由来	homo sapiens (ヒト)
キーワード	OXIDOREDUCTASE / Filament / Dehydrogenase / CBS domain / Bateman domain / purine biosynthesis