6SPT

High resolution crystal structure of N-terminal domain of PEX14 from Trypanosoma brucei in complex with the fist compound with sub-micromolar trypanocidal activity

6SPT の概要

• エントリーDOI: 10.2210/pdb6spt/pdb
• 分子名称: Peroxin 14, 5-[(4-methoxynaphthalen-1-yl)methyl]-1-[2-[(2-methyl-1-oxidanyl-propan-2-yl)amino]ethyl]-~{N}-(naphthalen-1-ylmethyl)-6,7-dihydro-4~{H}-pyrazolo[4,3-c]pyridine-3-carboxamide, BETA-MERCAPTOETHANOL, ... (5 entities in total)
• 機能のキーワード: pex5-pex14 protein protein inhibitor, hat, peroxisome, trypanosoma, signaling protein
• 由来する生物種: Trypanosoma brucei brucei
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 8851.03

構造登録者

Napolitano, V.,Dawidowski, M.,Kalel, V.C.,Fino, R.,Emmanouilidis, L.,Lenhart, D.,Ostertag, M.,Kaiser, M.,Kolonko, M.,Schilebs, W.,Maser, P.,Tetko, I.,Hadian, K.,Plettenburg, O.,Erdmann, R.,Sattler, M.,Popowicz, G.M.,Dubin, G. (登録日: 2019-09-02, 公開日: 2020-01-01, 最終更新日: 2020-02-05)

主引用文献

Dawidowski, M.,Kalel, V.C.,Napolitano, V.,Fino, R.,Schorpp, K.,Emmanouilidis, L.,Lenhart, D.,Ostertag, M.,Kaiser, M.,Kolonko, M.,Tippler, B.,Schliebs, W.,Dubin, G.,Maser, P.,Tetko, I.V.,Hadian, K.,Plettenburg, O.,Erdmann, R.,Sattler, M.,Popowicz, G.M.
Structure-Activity Relationship in Pyrazolo[4,3-c]pyridines, First Inhibitors of PEX14-PEX5 Protein-Protein Interaction with Trypanocidal Activity.
J.Med.Chem., 63:847-879, 2020

PubMed Abstract: protists are pathogens leading to a spectrum of devastating infectious diseases. The range of available chemotherapeutics against is limited, and the existing therapies are partially ineffective and cause serious adverse effects. Formation of the PEX14-PEX5 complex is essential for protein import into the parasites' glycosomes. This transport is critical for parasite metabolism and failure leads to mislocalization of glycosomal enzymes, with fatal consequences for the parasite. Hence, inhibiting the PEX14-PEX5 protein-protein interaction (PPI) is an attractive way to affect multiple metabolic pathways. Herein, we have used structure-guided computational screening and optimization to develop the first line of compounds that inhibit PEX14-PEX5 PPI. The optimization was driven by several X-ray structures, NMR binding data, and molecular dynamics simulations. Importantly, the developed compounds show significant cellular activity against , including the human pathogen and parasites.

PubMed: 31860309
DOI: 10.1021/acs.jmedchem.9b01876

実験手法

X-RAY DIFFRACTION (1.2 Å)