8HUG

F1 in complex with CRM1-Ran-RanBP1

8HUG の概要

• エントリーDOI: 10.2210/pdb8hug/pdb
• 分子名称: GTP-binding nuclear protein Ran, YRB1 isoform 1, CRM1 isoform 1, ... (10 entities in total)
• 機能のキーワード: active ran, complex, transport protein, inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 157690.77

構造登録者

Sun, Q.,Lei, Y. (登録日: 2022-12-23, 公開日: 2023-12-27, 最終更新日: 2024-07-10)

主引用文献

Li, C.,Zhang, Q.,Huang, W.,Huang, L.,Long, Q.,Lei, Y.,Jia, D.,Yang, S.,Yang, Y.,Zhang, X.,Sun, Q.
Discovery of a Hidden Pocket beneath the NES Groove by Novel Noncovalent CRM1 Inhibitors.
J.Med.Chem., 66:17044-17058, 2023

PubMed Abstract: Protein localization is frequently manipulated to favor tumor initiation and progression. In cancer cells, the nuclear export factor CRM1 is often overexpressed and aberrantly localizes many tumor suppressors via protein-protein interactions. Although targeting protein-protein interactions is usually challenging, covalent inhibitors, including the FDA-approved drug KPT-330 (selinexor), were successfully developed. The development of noncovalent CRM1 inhibitors remains scarce. Here, by shifting the side chain of two methionine residues and virtually screening against a large compound library, we successfully identified a series of noncovalent CRM1 inhibitors with a stable scaffold. Crystal structures of inhibitor-protein complexes revealed that one of the compounds, B28, utilized a deeply hidden protein interior cavity for binding. SAR analysis guided the development of several B28 derivatives with enhanced inhibition on nuclear export and growth of multiple cancer cell lines. This work may benefit the development of new CRM1-targeted therapies.

PubMed: 38105606
DOI: 10.1021/acs.jmedchem.3c01867

実験手法

X-RAY DIFFRACTION (2.15 Å)