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- PDB-9gge: Structure of the A467T mutant of human mitochondrial DNA polymera... -

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Basic information

Entry
Database: PDB / ID: 9gge
TitleStructure of the A467T mutant of human mitochondrial DNA polymerase gamma
Components
  • (DNA polymerase subunit gamma- ...) x 2
  • DNA (primer strand)
  • DNA (template strand)
KeywordsTRANSFERASE/DNA / Mitochondrial DNA polymerase / activator / TRANSFERASE-DNA complex
Function / homology
Function and homology information


gamma DNA polymerase complex / mitochondrial chromosome / Strand-asynchronous mitochondrial DNA replication / mitochondrial DNA replication / positive regulation of DNA-directed DNA polymerase activity / DNA replication proofreading / single-stranded DNA 3'-5' DNA exonuclease activity / Hydrolases; Acting on ester bonds; Exodeoxyribonucleases producing 5'-phosphomonoesters / DNA metabolic process / DNA polymerase processivity factor activity ...gamma DNA polymerase complex / mitochondrial chromosome / Strand-asynchronous mitochondrial DNA replication / mitochondrial DNA replication / positive regulation of DNA-directed DNA polymerase activity / DNA replication proofreading / single-stranded DNA 3'-5' DNA exonuclease activity / Hydrolases; Acting on ester bonds; Exodeoxyribonucleases producing 5'-phosphomonoesters / DNA metabolic process / DNA polymerase processivity factor activity / Lyases; Carbon-oxygen lyases; Other carbon-oxygen lyases / mitochondrial nucleoid / 5'-deoxyribose-5-phosphate lyase activity / base-excision repair, gap-filling / DNA polymerase binding / 3'-5' exonuclease activity / Transcriptional activation of mitochondrial biogenesis / base-excision repair / DNA-templated DNA replication / protease binding / double-stranded DNA binding / in utero embryonic development / DNA-directed DNA polymerase / DNA-directed DNA polymerase activity / mitochondrial matrix / intracellular membrane-bounded organelle / chromatin binding / protein-containing complex / mitochondrion / DNA binding / identical protein binding / cytoplasm
Similarity search - Function
DNA-directed DNA-polymerase, family A, mitochondria / DNA mitochondrial polymerase, exonuclease domain / POLG2, C-terminal / : / DNA mitochondrial polymerase exonuclease domain / Glycyl-tRNA synthetase/DNA polymerase subunit gamma-2 / Anticodon-binding / Anticodon binding domain / Anticodon-binding domain superfamily / DNA-directed DNA polymerase, family A, conserved site ...DNA-directed DNA-polymerase, family A, mitochondria / DNA mitochondrial polymerase, exonuclease domain / POLG2, C-terminal / : / DNA mitochondrial polymerase exonuclease domain / Glycyl-tRNA synthetase/DNA polymerase subunit gamma-2 / Anticodon-binding / Anticodon binding domain / Anticodon-binding domain superfamily / DNA-directed DNA polymerase, family A, conserved site / DNA polymerase family A signature. / DNA-directed DNA polymerase, family A, palm domain / DNA polymerase A domain / Class II Aminoacyl-tRNA synthetase/Biotinyl protein ligase (BPL) and lipoyl protein ligase (LPL) / Ribonuclease H-like superfamily / DNA/RNA polymerase superfamily
Similarity search - Domain/homology
2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE / DNA / DNA (> 10) / DNA polymerase subunit gamma-1 / DNA polymerase subunit gamma-2
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.69 Å
AuthorsValenzuela, S. / Falkenberg, M.
Funding support Sweden, 3items
OrganizationGrant numberCountry
Swedish Research Council Sweden
Knut and Alice Wallenberg Foundation Sweden
Cancerfonden Sweden
CitationJournal: Nature / Year: 2025
Title: Small molecules restore mutant mitochondrial DNA polymerase activity.
Authors: Sebastian Valenzuela / Xuefeng Zhu / Bertil Macao / Mattias Stamgren / Carol Geukens / Paul S Charifson / Gunther Kern / Emily Hoberg / Louise Jenninger / Anja V Gruszczyk / Seoeun Lee / ...Authors: Sebastian Valenzuela / Xuefeng Zhu / Bertil Macao / Mattias Stamgren / Carol Geukens / Paul S Charifson / Gunther Kern / Emily Hoberg / Louise Jenninger / Anja V Gruszczyk / Seoeun Lee / Katarina A S Johansson / Javier Miralles Fusté / Yonghong Shi / S Jordan Kerns / Laleh Arabanian / Gabriel Martinez Botella / Sofie Ekström / Jeremy Green / Andrew M Griffin / Carlos Pardo-Hernández / Thomas A Keating / Barbara Küppers-Munther / Nils-Göran Larsson / Cindy Phan / Viktor Posse / Juli E Jones / Xie Xie / Simon Giroux / Claes M Gustafsson / Maria Falkenberg /
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 ...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.
History
DepositionAug 13, 2024Deposition site: PDBE / Processing site: PDBE
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DNA polymerase subunit gamma-1
B: DNA polymerase subunit gamma-2
C: DNA polymerase subunit gamma-2
P: DNA (primer strand)
T: DNA (template strand)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)264,9697
Polymers264,4625
Non-polymers5072
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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DNA polymerase subunit gamma- ... , 2 types, 3 molecules ABC

#1: Protein DNA polymerase subunit gamma-1 / 3'-5' exodeoxyribonuclease / 5'-deoxyribose-phosphate lyase / Mitochondrial DNA polymerase ...3'-5' exodeoxyribonuclease / 5'-deoxyribose-phosphate lyase / Mitochondrial DNA polymerase catalytic subunit / PolG-alpha


Mass: 138074.672 Da / Num. of mol.: 1 / Mutation: A467T
Source method: isolated from a genetically manipulated source
Details: A467T mutant / Source: (gene. exp.) Homo sapiens (human) / Gene: POLG, MDP1, POLG1, POLGA / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P54098, DNA-directed DNA polymerase, Hydrolases; Acting on ester bonds; Exodeoxyribonucleases producing 5'-phosphomonoesters, Lyases; Carbon-oxygen lyases; Other carbon-oxygen lyases
#2: Protein DNA polymerase subunit gamma-2 / DNA polymerase gamma accessory 55 kDa subunit / p55 / Mitochondrial DNA polymerase accessory ...DNA polymerase gamma accessory 55 kDa subunit / p55 / Mitochondrial DNA polymerase accessory subunit / MtPolB / PolG-beta


Mass: 53229.684 Da / Num. of mol.: 2 / Mutation: A169T
Source method: isolated from a genetically manipulated source
Details: A169T (Single Nucleotide Polymorphism) / Source: (gene. exp.) Homo sapiens (human) / Gene: POLG2, MTPOLB / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9UHN1

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DNA chain , 2 types, 2 molecules PT

#3: DNA chain DNA (primer strand)


Mass: 7764.998 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#4: DNA chain DNA (template strand)


Mass: 12162.783 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 2 types, 2 molecules

#5: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-DCP / 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE


Mass: 467.157 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H16N3O13P3 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Structure of the A467T mutant of human mitochondrial DNA polymerase gamma
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.3.1.particle selection
2EPUimage acquisition
4cryoSPARC4.3.1.CTF correction
8PHENIXmodel refinement
10cryoSPARC4.3.1.initial Euler assignment
11cryoSPARC4.3.1.final Euler assignment
13cryoSPARC4.3.1.3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.69 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 581937 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00214286
ELECTRON MICROSCOPYf_angle_d0.40319527
ELECTRON MICROSCOPYf_dihedral_angle_d12.1715332
ELECTRON MICROSCOPYf_chiral_restr0.0372099
ELECTRON MICROSCOPYf_plane_restr0.0042369

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