2BJU

Plasmepsin II complexed with a highly active achiral inhibitor

2BJU の概要

• エントリーDOI: 10.2210/pdb2bju/pdb
• 関連するPDBエントリー: 1J8J 1LEE 1LF2 1LF3 1LF4 1M43 1ME6 1PFZ 1SME 1W6H 1W6I
• 分子名称: PLASMEPSIN II, N-(R-CARBOXY-ETHYL)-ALPHA-(S)-(2-PHENYLETHYL) (3 entities in total)
• 機能のキーワード: plasmepsin, aspartic proteinase, drug design, malaria, aspartyl protease, glycoprotein, hydrolase, zymogen
• 由来する生物種: PLASMODIUM FALCIPARUM
• 細胞内の位置: Vacuole: P46925
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 52727.99

構造登録者

Prade, L.,Jones, A.F.,Boss, C.,Richards-Bildstein, S.,Meyer, S.,Binkert, C.,Bur, D. (登録日: 2005-02-08, 公開日: 2005-04-18, 最終更新日: 2024-11-06)

主引用文献

Prade, L.,Jones, A.F.,Boss, C.,Richard-Bildstein, S.,Meyer, S.,Binkert, C.,Bur, D.
X-Ray Structure of Plasmepsin II Complexed with a Potent Achiral Inhibitor.
J.Biol.Chem., 280:23837-, 2005

PubMed Abstract: The malaria parasite Plasmodium falciparum degrades host cell hemoglobin inside an acidic food vacuole during the blood stage of the infectious cycle. A number of aspartic proteinases called plasmepsins (PMs) have been identified to play important roles in this degradation process and therefore generated significant interest as new antimalarial targets. Several x-ray structures of PMII have been described previously, but thus far, structure-guided drug design has been hampered by the fact that only inhibitors comprising a statine moiety or derivatives thereof have been published. Our drug discovery efforts to find innovative, cheap, and easily synthesized inhibitors against aspartic proteinases yielded some highly potent non-peptidic achiral inhibitors. A highly resolved (1.6 A) x-ray structure of PMII is presented, featuring a potent achiral inhibitor in an unprecedented orientation, contacting the catalytic aspartates indirectly via the "catalytic" water. Major side chain rearrangements in the active site occur, which open up a new pocket and allow a new binding mode of the inhibitor. Moreover, a second inhibitor molecule could be located unambiguously in the active site of PMII. These newly obtained structural insights will further guide our attempts to improve compound properties eventually leading to the identification of molecules suitable as antimalarial drugs.

PubMed: 15840589
DOI: 10.1074/JBC.M501519200

実験手法

X-RAY DIFFRACTION (1.56 Å)