6LQ9

S109 in complex with CRM1-Ran-RanBP1

Summary for 6LQ9

• Entry DOI: 10.2210/pdb6lq9/pdb
• Descriptor: GTP-binding nuclear protein Ran, Ran-specific GTPase-activating protein 1, Exportin-1, ... (10 entities in total)
• Functional Keywords: transport protein, nuclear export, complex, mutant, activation
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 161767.70

Authors

Sun, Q.,Lei, Y. (deposition date: 2020-01-13, release date: 2021-06-23, Last modification date: 2024-11-06)

Primary citation

Lei, Y.,An, Q.,Shen, X.F.,Sui, M.,Li, C.,Jia, D.,Luo, Y.,Sun, Q.
Structure-Guided Design of the First Noncovalent Small-Molecule Inhibitor of CRM1.
J.Med.Chem., 64:6596-6607, 2021

PubMed Abstract: Nuclear export factor chromosome region maintenance 1 (CRM1) is an attractive anticancer and antiviral drug target that spurred several research efforts to develop its inhibitor. Noncovalent CRM1 inhibitors are desirable, but none is reported to date. Here, we present the crystal structure of yeast CRM1 in complex with S109, a substructure of CBS9106 (under clinical test). Superimposition with the LFS-829 (another covalent CRM1 inhibitor) complex inspired the design of a noncovalent CRM1 inhibitor. Among nine synthesized compounds, noncovalent CRM1 inhibitor 1 (NCI-1) showed a high affinity to human and yeast CRM1 in the absence or presence of GST-bound Ras-related nuclear protein (RanGTP). Unlike covalent inhibitors, the crystal structure showed that NCI-1 is bound in the "open" nuclear export signal (NES) groove of CRM1, simultaneously occupying two hydrophobic pockets. NCI-1 additionally inhibited the nuclear export and proliferation of cells harboring the human CRM1-C528S mutant. Our work opens up the avenue of noncovalent CRM1 inhibitor development toward a more potent, less toxic, and broad-spectrum anticancer/antiviral therapy.

PubMed: 33974430
DOI: 10.1021/acs.jmedchem.0c01675

Experimental method

X-RAY DIFFRACTION (2.5 Å)