title: Crystal Structure of the Apicoplast DNA Polymerase from Plasmodium falciparum: The First Look at a Plastidic A-Family DNA Polymerase.
abstract: Plasmodium falciparum, the primary cause of malaria, contains a non-photosynthetic plastid called the apicoplast. The apicoplast exists in most members of the phylum Apicomplexa and has its own genome along with organelle-specific enzymes for its replication. The only DNA polymerase found in the apicoplast (apPOL) was putatively acquired through horizontal gene transfer from a bacteriophage and is classified as an atypical A-family polymerase. Here, we present its crystal structure at a resolution of 2.9Å. P. falciparum apPOL, the first structural representative of a plastidic A-family polymerase, diverges from typical A-family members in two of three previously identified signature motifs and in a region not implicated by sequence. Moreover, apPOL has an additional N-terminal subdomain, the absence of which severely diminishes its 3' to 5' exonuclease activity. A compound known to be toxic to Plasmodium is a potent inhibitor of apPOL, suggesting that apPOL is a viable drug target. The structure provides new insights into the structural diversity of A-family polymerases and may facilitate structurally guided antimalarial drug design.
authors.affiliation: Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, IA 50011, USA.
authors.forename: Morgan E
authors.initials: ME
authors.lastname: Milton
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
authors.forename: Jun-Yong
authors.initials: JY
authors.lastname: Choe
authors.affiliation: Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, IA 50011, USA. Electronic address: honzatko@iastate.edu.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Honzatko
authors.affiliation: Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, IA 50011, USA. Electronic address: swn@iastate.edu.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Nelson
mesh_terms: D063546:Apicoplasts / Q000201:enzymology*; D018360:Crystallography, X-Ray; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry*; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000201:enzymology*; D011487:Protein Conformation; D000072417:Protein Domains
chemical_list: D004259:DNA-Directed DNA Polymerase
keywords: DNA exonuclease; DNA–protein interactions; Enzyme catalysis; bifunctional enzymes; malaria