7SXQ

Plasmodium falciparum apicoplast DNA polymerase (exo-minus) without affinity tag

7SXQ の概要

• エントリーDOI: 10.2210/pdb7sxq/pdb
• 関連するPDBエントリー: 5DKU
• 分子名称: Apicoplast DNA polymerase, DI(HYDROXYETHYL)ETHER, CHLORIDE ION, ... (6 entities in total)
• 機能のキーワード: dna polymerase, exonulease, apicoplast, plasmodium falciparum, replication, transferase
• 由来する生物種: Plasmodium falciparum (isolate 3D7)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 148672.95

構造登録者

Nieto, N.,Chheda, P.,Kerns, R.,Nelson, S.,Honzatko, R. (登録日: 2021-11-24, 公開日: 2022-10-19, 最終更新日: 2023-10-18)

主引用文献

Chheda, P.R.,Nieto, N.,Kaur, S.,Beck, J.M.,Beck, J.R.,Honzatko, R.,Kerns, R.J.,Nelson, S.W.
Promising antimalarials targeting apicoplast DNA polymerase from Plasmodium falciparum.
Eur.J.Med.Chem., 243:114751-114751, 2022

PubMed Abstract: Malaria is caused by the parasite Plasmodium falciparum, which contains an essential non-photosynthetic plastid called the apicoplast. A single DNA polymerase, apPOL, is targeted to the apicoplast, where it replicates and repairs the genome. apPOL has no direct orthologs in mammals and is considered a promising drug target for the treatment and/or prevention of malaria. We previously reported screening the Malaria Box to identify MMV666123 as an inhibitor of apPOL. Herein we extend our studies and report structure-activity relationships for MMV666123 and identify key structural motifs necessary for inhibition. Although attempts to crystallize apPOL with the inhibitor were not fruitful, kinetic analysis and crystal structure determinations of WT and mutant apo-enzymes, facilitated model building and provided insights into the putative inhibitor binding site. Our results validate apPOL as an antimalarial target and provide an avenue for the design of high potency, specific inhibitors of apPOL and other A-family DNA polymerases.

PubMed: 36191407
DOI: 10.1016/j.ejmech.2022.114751

実験手法

X-RAY DIFFRACTION (2.5 Å)