6CIT

Crystal Structure of MVM NS2 NES Peptide in complex with CRM1-Ran-RanBP1

6CIT の概要

• エントリーDOI: 10.2210/pdb6cit/pdb
• 分子名称: GTP-binding nuclear protein Ran, Ran-specific GTPase-activating protein 1, Exportin-1, ... (9 entities in total)
• 機能のキーワード: karyopherin, crm1, xpo1, exportin-1, mvm, nes, nuclear export, protein transport
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 164164.26

構造登録者

Fung, H.Y.J.,Chook, Y.M. (登録日: 2018-02-25, 公開日: 2018-06-27, 最終更新日: 2023-10-04)

主引用文献

Fu, S.C.,Fung, H.Y.J.,Cagatay, T.,Baumhardt, J.,Chook, Y.M.
Correlation of CRM1-NES affinity with nuclear export activity.
Mol. Biol. Cell, 29:2037-2044, 2018

PubMed Abstract: CRM1 (Exportin1/XPO1) exports hundreds of broadly functioning protein cargoes out of the cell nucleus by binding to their classical nuclear export signals (NESs). The 8- to 15-amino-acid-long NESs contain four to five hydrophobic residues and are highly diverse in both sequence and CRM1-bound structure. Here we examine the relationship between nuclear export activities of 24 different NES peptides in cells and their CRM1-NES affinities. We found that binding affinity and nuclear export activity are linearly correlated for NESs with dissociation constants ( Ks) between tens of nanomolar to tens of micromolar. NESs with Ks outside this range have significantly reduced nuclear export activities. These include two unusually tight-binding peptides, one from the nonstructural protein 2 of murine minute virus (MVM NS2) and the other a mutant of the protein kinase A inhibitor (PKI) NES. The crystal structure of CRM1-bound MVM NS2 suggests that extraordinarily tight CRM1 binding arises from intramolecular contacts within the NES that likely stabilizes the CRM1-bound conformation in free peptides. This mechanistic understanding led to the design of two novel peptide inhibitors that bind CRM1 with picomolar affinity.

PubMed: 29927350
DOI: 10.1091/mbc.E18-02-0096

実験手法

X-RAY DIFFRACTION (2.027 Å)