9GGD

Structure of the A467T mutant of human mitochondrial DNA polymerase gamma in complex with PZL-A

This is a non-PDB format compatible entry.

Summary for 9GGD

• Entry DOI: 10.2210/pdb9ggd/pdb
• Related: 9GGB 9GGC 9GGE 9GGF
• EMDB information: 51326 51327 51328 51329 51330
• Descriptor: DNA polymerase subunit gamma-1, DNA polymerase subunit gamma-2, DNA (primer strand), ... (7 entities in total)
• Functional Keywords: mitochondrial dna polymerase, activator, transferase/dna, transferase-dna complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 265337.87

Authors

Valenzuela, S.,Falkenberg, M. (deposition date: 2024-08-13, release date: 2025-04-16, Last modification date: 2025-04-23)

Primary citation

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, 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

Experimental method

ELECTRON MICROSCOPY (2.67 Å)