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TitleCryo-EM Structures of the Plasmodium falciparum Apicoplast DNA Polymerase.
Journal, issue, pagesJ Mol Biol, Vol. 436, Issue 23, Page 168842, Year 2024
Publish dateDec 1, 2024
AuthorsChen-Yu Lo / Adron R Ung / Tirthankar Koley / Scott W Nelson / Yang Gao /
PubMed AbstractThe apicoplast DNA polymerase (apPol) from Plasmodium falciparum is essential for the parasite's survival, making it a prime target for antimalarial therapies. Here, we present cryo-electron ...The apicoplast DNA polymerase (apPol) from Plasmodium falciparum is essential for the parasite's survival, making it a prime target for antimalarial therapies. Here, we present cryo-electron microscopy structures of the apPol in complex with DNA and incoming nucleotide, offering insights into its molecular mechanisms. Our structural analysis reveals that apPol contains critical residues for high-fidelity DNA synthesis, but lacks certain structural elements to confer processive DNA synthesis during replication, suggesting the presence of additional accessory factors. The enzyme exhibits large-scale conformational changes upon DNA and nucleotide binding, particularly within the fingers and thumb subdomains. These movements reveal potential allosteric sites that could serve as targets for drug design. Our findings provide a foundation for advancing the understanding of apPol's unique functional mechanisms and potentially offering new avenues for the development of novel inhibitors and therapeutic interventions against malaria.
External linksJ Mol Biol / PubMed:39490679 / PubMed Central
MethodsEM (single particle)
Resolution3.17 - 5.2 Å
Structure data

45407

9cay

EMDB-45407, PDB-9cay:
Ternary structure of Plasmodium falciparum apicoplast DNA polymerase (exo-minus)
Method: EM (single particle) / Resolution: 3.17 Å

46821

9dg1

EMDB-46821, PDB-9dg1:
Structure of Plasmodium falciparum apicoplast DNA polymerase in complex with DNA (exo-minus)
Method: EM (single particle) / Resolution: 5.2 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-DGT:
2'-DEOXYGUANOSINE-5'-TRIPHOSPHATE

Source
  • Plasmodium falciparum (malaria parasite P. falciparum)
  • homo sapiens (human)
  • plasmodium falciparum (isolate 3d7) (eukaryote)
  • plasmodium falciparum 3d7 (eukaryote)
KeywordsDNA BINDING PROTEIN/DNA / DNA polymerase / DNA BINDING PROTEIN / DNA BINDING PROTEIN-DNA complex

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