6M60

Plumbagin in complex with CRM1#-Ran-RanBP1

6M60 の概要

• エントリーDOI: 10.2210/pdb6m60/pdb
• 関連するPDBエントリー: 5YSU
• 分子名称: GTP-binding nuclear protein Ran, (2~{R})-2-methyl-5-oxidanyl-2,3-dihydronaphthalene-1,4-dione, Ran-specific GTPase-activating protein 1, ... (11 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: 158223.40

構造登録者

Sun, Q.,Lei, Y. (登録日: 2020-03-12, 公開日: 2021-06-09, 最終更新日: 2024-10-30)

主引用文献

Lei, Y.,Li, Y.,Tan, Y.,Qian, Z.,Zhou, Q.,Jia, D.,Sun, Q.
Novel Mechanistic Observations and NES-Binding Groove Features Revealed by the CRM1 Inhibitors Plumbagin and Oridonin.
J.Nat.Prod., 84:1478-1488, 2021

PubMed Abstract: The protein chromosome region maintenance 1 (CRM1) is an important nuclear export factor and drug target in diseases such as cancer and viral infections. Several plant-derived CRM1 inhibitors including plumbagin and oridonin possess potent antitumor activities. However, their modes of CRM1 inhibition remain unclear. Here, a multimutant CRM1 was engineered to enable crystallization of these two small molecules in its NES groove. Plumbagin and oridonin share the same three conjugation sites in CRM1. In solution, these two inhibitors targeted more CRM1 sites and inhibited its activity through promoting its aggregation, in addition to directly targeting the NES groove. While the plumbagin-bound NES groove resembles the NES-bound groove state, the oridonin complex reveals for the first time a more open NES groove. The observed greater NES groove dynamics may improve cargo loading through a "capture-and-tighten" mechanism. This work thus provides new insights on the mechanism of CRM1 inhibition by two natural products and a structural basis for further development of these or other CRM1 inhibitors.

PubMed: 33890470
DOI: 10.1021/acs.jnatprod.0c01231

実験手法

X-RAY DIFFRACTION (2.17 Å)