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- EMDB-51326: Structure of the G848S mutant of human mitochondrial DNA polymera... -

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Basic information

Entry
Database: EMDB / ID: EMD-51326
TitleStructure of the G848S mutant of human mitochondrial DNA polymerase gamma in complex with PZL-A
Map data
Sample
  • Complex: Structure of the G848S mutant of human mitochondrial DNA polymerase gamma in complex with PZL-A
    • Complex: DNA polymerase gamma
      • Protein or peptide: DNA polymerase subunit gamma-1
      • Protein or peptide: DNA polymerase subunit gamma-2
    • Complex: DNA
      • DNA: DNA (primer strand)
      • DNA: DNA (template strand)
  • Ligand: CALCIUM ION
  • Ligand: 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE
  • Ligand: 1-[(4S)-8-chloranyl-3,4-dihydro-2H-chromen-4-yl]-3-(1-phenylpyrazol-3-yl)urea
KeywordsMitochondrial DNA polymerase / activator / TRANSFERASE/DNA / 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 / mitochondrial nucleoid / Lyases; Carbon-oxygen lyases; Other carbon-oxygen lyases / 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 / double-stranded DNA binding / protease 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
DNA polymerase subunit gamma-1 / DNA polymerase subunit gamma-2
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.63 Å
AuthorsValenzuela S / Falkenberg M
Funding support Sweden, 3 items
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: Valenzuela S / Zhu X / Macao B / Stamgren M / Geukens C / Charifson PS / Kern G / Hoberg E / Jenninger L / Gruszczyk AV / Lee S / Johansson KAS / Miralles Fuste J / Shi Y / Kerns SJ / ...Authors: Valenzuela S / Zhu X / Macao B / Stamgren M / Geukens C / Charifson PS / Kern G / Hoberg E / Jenninger L / Gruszczyk AV / Lee S / Johansson KAS / Miralles Fuste J / Shi Y / Kerns SJ / Arabanian L / Martinez Botella G / Ekstrom S / Green J / Griffin AM / Pardo-Hernandez C / Keating TA / Kuppers-Munther B / Larsson NG / Phan C / Posse V / Jones JE / Xie X / Giroux S / Gustafsson CM / Falkenberg M
History
DepositionAug 13, 2024-
Header (metadata) releaseApr 16, 2025-
Map releaseApr 16, 2025-
UpdateJul 9, 2025-
Current statusJul 9, 2025Processing site: PDBe / Status: Released

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Structure visualization

Downloads & links

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Map

FileDownload / File: emd_51326.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.825 Å
Density
Contour LevelBy AUTHOR: 3.5
Minimum - Maximum-34.368504000000001 - 47.506439999999998
Average (Standard dev.)0.0013075704 (±0.97593397)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 264.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Structure of the G848S mutant of human mitochondrial DNA polymera...

EntireName: Structure of the G848S mutant of human mitochondrial DNA polymerase gamma in complex with PZL-A
Components
  • Complex: Structure of the G848S mutant of human mitochondrial DNA polymerase gamma in complex with PZL-A
    • Complex: DNA polymerase gamma
      • Protein or peptide: DNA polymerase subunit gamma-1
      • Protein or peptide: DNA polymerase subunit gamma-2
    • Complex: DNA
      • DNA: DNA (primer strand)
      • DNA: DNA (template strand)
  • Ligand: CALCIUM ION
  • Ligand: 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE
  • Ligand: 1-[(4S)-8-chloranyl-3,4-dihydro-2H-chromen-4-yl]-3-(1-phenylpyrazol-3-yl)urea

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Supramolecule #1: Structure of the G848S mutant of human mitochondrial DNA polymera...

SupramoleculeName: Structure of the G848S mutant of human mitochondrial DNA polymerase gamma in complex with PZL-A
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4

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Supramolecule #2: DNA polymerase gamma

SupramoleculeName: DNA polymerase gamma / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: DNA

SupramoleculeName: DNA / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3-#4
Source (natural)Organism: synthetic construct (others)

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Macromolecule #1: DNA polymerase subunit gamma-1

MacromoleculeName: DNA polymerase subunit gamma-1 / type: protein_or_peptide / ID: 1 / Details: G848S mutant / Number of copies: 1 / Enantiomer: LEVO / EC number: DNA-directed DNA polymerase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 138.074672 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHHHVSS SVPASDPSDG QRRRQQQQQQ QQQQQQQPQQ PQVLSSEGGQ LRHNPLDIQM LSRGLHEQIF GQGGEMPGEA AVRRSVEHL QKHGLWGQPA VPLPDVELRL PPLYGDNLDQ HFRLLAQKQS LPYLEAANLL LQAQLPPKPP AWAWAEGWTR Y GPEGEAVP ...String:
MHHHHHHVSS SVPASDPSDG QRRRQQQQQQ QQQQQQQPQQ PQVLSSEGGQ LRHNPLDIQM LSRGLHEQIF GQGGEMPGEA AVRRSVEHL QKHGLWGQPA VPLPDVELRL PPLYGDNLDQ HFRLLAQKQS LPYLEAANLL LQAQLPPKPP AWAWAEGWTR Y GPEGEAVP VAIPEERALV FDVEVCLAEG TCPTLAVAIS PSAWYSWCSQ RLVEERYSWT SQLSPADLIP LEVPTGASSP TQ RDWQEQL VVGHNVSFDR AHIREQYLIQ GSRMRFLDTM SMHMAISGLS SFQRSLWIAA KQGKHKVQPP TKQGQKSQRK ARR GPAISS WDWLDISSVN SLAEVHRLYV GGPPLEKEPR ELFVKGTMKD IRENFQDLMQ YCAQDVWATH EVFQQQLPLF LERC PHPVT LAGMLEMGVS YLPVNQNWER YLAEAQGTYE ELQREMKKSL MDLANDACQL LSGERYKEDP WLWDLEWDLQ EFKQK KAKK VKKEPATASK LPIEGAGAPG DPMDQEDLGP CSEEEEFQQD VMARACLQKL KGTTELLPKR PQHLPGHPGW YRKLCP RLD DPAWTPGPSL LSLQMRVTPK LMALTWDGFP LHYSERHGWG YLVPGRRDNL AKLPTGTTLE SAGVVCPYRA IESLYRK HC LEQGKQQLMP QEAGLAEEFL LTDNSAIWQT VEELDYLEVE AEAKMENLRA AVPGQPLALT ARGGPKDTQP SYHHGNGP Y NDVDIPGCWF FKLPHKDGNS CNVGSPFAKD FLPKMEDGTL QAGPGGASGP RALEINKMIS FWRNAHKRIS SQMVVWLPR SALPRAVIRH PDYDEEGLYG AILPQVVTAS TITRRAVEPT WLTASNARPD RVGSELKAMV QAPPGYTLVG ADVDSQELWI AAVLGDAHF AGMHGCTAFG WMTLQGRKSR GTDLHSKTAT TVGISREHAK IFNYGRIYGA GQPFAERLLM QFNHRLTQQE A AEKAQQMY AATKGLRWYR LSDEGEWLVR ELNLPVDRTE GGWISLQDLR KVQRETARKS QWKKWEVVAE RAWKGGTESE MF NKLESIA TSDIPRTPVL GCCISRALEP SAVQEEFMTS RVNWVVQSSA VDYLHLMLVA MKWLFEEFAI DGRFCISIHD EVR YLVREE DRYRAALALQ ITNLLTRCMF AYKLGLNDLP QSVAFFSAVD IDRCLRKEVT MDCKTPSNPT GMERRYGIPQ GEAL DIYQI IELTKGSLEK RSQPGP

UniProtKB: DNA polymerase subunit gamma-1

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Macromolecule #2: DNA polymerase subunit gamma-2

MacromoleculeName: DNA polymerase subunit gamma-2 / type: protein_or_peptide / ID: 2 / Details: A169T (Single Nucleotide Polymorphism) / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 53.229684 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MDAGQPELLT ERSSPKGGHV KSHAELEGNG EHPEAPGSGE GSEALLEICQ RRHFLSGSKQ QLSRDSLLSG CHPGFGPLGV ELRKNLAAE WWTSVVVFRE QVFPVDALHH KPGPLLPGDS AFRLVSAETL REILQDKELS KEQLVTFLEN VLKTSGKLRE N LLHGALEH ...String:
MDAGQPELLT ERSSPKGGHV KSHAELEGNG EHPEAPGSGE GSEALLEICQ RRHFLSGSKQ QLSRDSLLSG CHPGFGPLGV ELRKNLAAE WWTSVVVFRE QVFPVDALHH KPGPLLPGDS AFRLVSAETL REILQDKELS KEQLVTFLEN VLKTSGKLRE N LLHGALEH YVNCLDLVNK RLPYGLAQIG VCFHPVFDTK QIRNGVKSIG EKTEASLVWF TPPRTSNQWL DFWLRHRLQW WR KFAMSPS NFSSSDCQDE EGRKGNKLYY NFPWGKELIE TLWNLGDHEL LHMYPGNVSK LHGRDGRKNV VPCVLSVNGD LDR GMLAYL YDSFQLTENS FTRKKNLHRK VLKLHPCLAP IKVALDVGRG PTLELRQVCQ GLFNELLENG ISVWPGYLET MQSS LEQLY SKYDEMSILF TVLVTETTLE NGLIHLRSRD TTMKEMMHIS KLKDFLIKYI SSAKNVHHHH HH

UniProtKB: DNA polymerase subunit gamma-2

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Macromolecule #3: DNA (primer strand)

MacromoleculeName: DNA (primer strand) / type: dna / ID: 3 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 7.764998 KDa
SequenceString:
(DG)(DC)(DA)(DT)(DG)(DC)(DG)(DG)(DT)(DC) (DG)(DA)(DG)(DT)(DC)(DT)(DA)(DG)(DA)(DG) (DG)(DA)(DG)(DC)(DC)

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Macromolecule #4: DNA (template strand)

MacromoleculeName: DNA (template strand) / type: dna / ID: 4 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 12.162783 KDa
SequenceString:
(DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT) (DA)(DT)(DC)(DC)(DG)(DG)(DG)(DC)(DT)(DC) (DC)(DT)(DC)(DT)(DA)(DG)(DA)(DC)(DT) (DC)(DG)(DA)(DC)(DC)(DG)(DC)(DA)(DT)(DG) (DC)

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Macromolecule #5: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #6: 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE

MacromoleculeName: 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE / type: ligand / ID: 6 / Number of copies: 1 / Formula: DCP
Molecular weightTheoretical: 467.157 Da
Chemical component information

ChemComp-DCP:
2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE

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Macromolecule #7: 1-[(4S)-8-chloranyl-3,4-dihydro-2H-chromen-4-yl]-3-(1-phenylpyraz...

MacromoleculeName: 1-[(4S)-8-chloranyl-3,4-dihydro-2H-chromen-4-yl]-3-(1-phenylpyrazol-3-yl)urea
type: ligand / ID: 7 / Number of copies: 1 / Formula: A1IK1
Molecular weightTheoretical: 368.817 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
GridModel: Quantifoil R2/1 / Material: COPPER / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 105000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 4.3.1.) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: Ab-initio model
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.63 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.3.1.) / Number images used: 893791
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.3.1.)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.3.1.)

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