9HHC

Crystal Structure of the Plasmodium falciparum Bromodomain PfBDP1 in complex with MPM2

9HHC の概要

• エントリーDOI: 10.2210/pdb9hhc/pdb
• 関連するPDBエントリー: 9HGF
• 分子名称: Bromodomain protein 1, (R,R)-2,3-BUTANEDIOL, 1-(3-aminophenyl)-3-methyl-5,6,7,8-tetrahydro-2~{H}-cyclohepta[c]pyrrol-4-one, ... (4 entities in total)
• 機能のキーワード: plasmodium, bromodomain, inhibitor, complex, transcription
• 由来する生物種: Plasmodium falciparum 3D7
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 16171.65

構造登録者

Amann, M.,Huegle, M.,Einsle, O.,Guenther, S. (登録日: 2024-11-21, 公開日: 2025-04-02, 最終更新日: 2025-06-11)

主引用文献

Amann, M.,Warstat, R.,Rechten, K.K.,Theuer, P.,Schustereder, M.,Clavey, S.,Breit, B.,Einsle, O.,Hugle, M.,Petter, M.,Gunther, S.
A Novel Inhibitor against the Bromodomain Protein 1 of the Malaria Pathogen Plasmodium Falciparum.
Chemmedchem, 20:e202500024-e202500024, 2025

PubMed Abstract: The rise of drug resistances in malaria necessitates the exploration of novel therapeutic strategies. Targeting epigenetic pathways could open new, promising treatment avenues. In this study, we focus on the essential Bromodomain Protein 1 (PfBDP1) of the malaria pathogen Plasmodium falciparum. Utilizing the pan-selective bromodomain inhibitor MPM6, we identified a potent initial hit and subsequently developed it into a nanomolar binder. Through a combination of virtual docking, isothermal titration calorimetry, and X-ray crystallography, we elucidated the molecular interactions of the new inhibitors with the bromodomain (BRD) of the protein (PfBDP1-BRD). Our findings include the first co-crystallized inhibitors with the structures of PfBRD1-BRD as well as the bromodomain of the close homologous protein of Plasmodium vivax (PvBDP1-BRD). The structures provide new insights into their binding mechanisms. Further validation using conditional knockdown of PfBDP1 in P. falciparum demonstrated parasite sensitivity to the inhibitor, underscoring its potential in a targeted therapeutic approach against malaria.

PubMed: 40099623
DOI: 10.1002/cmdc.202500024

実験手法

X-RAY DIFFRACTION (1.56 Å)