9GGF

Structure of WT human mitochondrial DNA polymerase gamma

9GGF の概要

• エントリーDOI: 10.2210/pdb9ggf/pdb
• 関連するPDBエントリー: 9GGB 9GGC 9GGD 9GGE
• EMDBエントリー: 51326 51327 51328 51329 51330
• 分子名称: DNA polymerase subunit gamma-1, DNA polymerase subunit gamma-2, DNA (primer strand), ... (6 entities in total)
• 機能のキーワード: mitochondrial dna polymerase, activator, transferase/dna, transferase-dna complex
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 264939.03

構造登録者

Valenzuela, S.,Falkenberg, M. (登録日: 2024-08-13, 公開日: 2025-04-16, 最終更新日: 2025-07-02)

主引用文献

Valenzuela, S.,Zhu, X.,Macao, B.,Stamgren, M.,Geukens, C.,Charifson, P.S.,Kern, G.,Hoberg, E.,Jenninger, L.,Gruszczyk, A.V.,Lee, S.,Johansson, K.A.S.,Miralles Fuste, J.,Shi, Y.,Kerns, S.J.,Arabanian, L.,Martinez Botella, G.,Ekstrom, S.,Green, J.,Griffin, A.M.,Pardo-Hernandez, C.,Keating, T.A.,Kuppers-Munther, B.,Larsson, N.G.,Phan, C.,Posse, V.,Jones, J.E.,Xie, X.,Giroux, S.,Gustafsson, C.M.,Falkenberg, M.
Small molecules restore mutant mitochondrial DNA polymerase activity.
Nature, 642:501-507, 2025

PubMed Abstract: Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase γ (POLγ), a heterotrimeric complex consisting of a catalytic POLγA subunit and two accessory POLγB subunits. More than 300 mutations in POLG, the gene encoding the catalytic subunit, have been linked to severe, progressive conditions with high rates of morbidity and mortality, for which no treatment exists. Here we report on the discovery and characterization of PZL-A, a first-in-class small-molecule activator of mtDNA synthesis that is capable of restoring function to the most common mutant variants of POLγ. PZL-A binds to an allosteric site at the interface between the catalytic POLγA subunit and the proximal POLγB subunit, a region that is unaffected by nearly all disease-causing mutations. The compound restores wild-type-like activity to mutant forms of POLγ in vitro and activates mtDNA synthesis in cells from paediatric patients with lethal POLG disease, thereby enhancing biogenesis of the oxidative phosphorylation machinery and cellular respiration. Our work demonstrates that a small molecule can restore function to mutant DNA polymerases, offering a promising avenue for treating POLG disorders and other severe conditions linked to depletion of mtDNA.

PubMed: 40205042
DOI: 10.1038/s41586-025-08856-9

実験手法

ELECTRON MICROSCOPY (2.65 Å)