7DBG

Yeast CRM1e (apo) in complex with Ran-RanBP1

Summary for 7DBG

• Entry DOI: 10.2210/pdb7dbg/pdb
• Descriptor: GTP-binding nuclear protein Ran, YRB1 isoform 1, CRM1 isoform 1, ... (10 entities in total)
• Functional Keywords: complex, transport protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 157467.82

Authors

Sun, Q.,Lei, Y. (deposition date: 2020-10-20, release date: 2021-09-29, Last modification date: 2023-11-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.06 Å)