4WVF

Crystal structure of KPT276 in complex with CRM1-Ran-RanBP1

4WVF の概要

• エントリーDOI: 10.2210/pdb4wvf/pdb
• 関連するPDBエントリー: 4gmx
• 分子名称: GTP-binding nuclear protein Ran, Ran-specific GTPase-activating protein 1, Crm1p, ... (10 entities in total)
• 機能のキーワード: crm1, inhibitor, sine, kpt, transport protein-transport protein inhibitor complex, transport protein/transport protein inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Nucleus: P62826; Cytoplasm: P41920
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 159820.35

構造登録者

Sun, Q.,Chook, Y. (登録日: 2014-11-05, 公開日: 2015-07-15, 最終更新日: 2024-10-23)

主引用文献

Haines, J.D.,Herbin, O.,de la Hera, B.,Vidaurre, O.G.,Moy, G.A.,Sun, Q.,Fung, H.Y.,Albrecht, S.,Alexandropoulos, K.,McCauley, D.,Chook, Y.M.,Kuhlmann, T.,Kidd, G.J.,Shacham, S.,Casaccia, P.
Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination.
Nat.Neurosci., 18:511-520, 2015

PubMed Abstract: Axonal damage has been associated with aberrant protein trafficking. We examined a newly characterized class of compounds that target nucleo-cytoplasmic shuttling by binding to the catalytic groove of the nuclear export protein XPO1 (also known as CRM1, chromosome region maintenance protein 1). Oral administration of reversible CRM1 inhibitors in preclinical murine models of demyelination significantly attenuated disease progression, even when started after the onset of paralysis. Clinical efficacy was associated with decreased proliferation of immune cells, characterized by nuclear accumulation of cell cycle inhibitors, and preservation of cytoskeletal integrity even in demyelinated axons. Neuroprotection was not limited to models of demyelination, but was also observed in another mouse model of axonal damage (that is, kainic acid injection) and detected in cultured neurons after knockdown of Xpo1, the gene encoding CRM1. A proteomic screen for target molecules revealed that CRM1 inhibitors in neurons prevented nuclear export of molecules associated with axonal damage while retaining transcription factors modulating neuroprotection.

PubMed: 25706475
DOI: 10.1038/nn.3953

実験手法

X-RAY DIFFRACTION (1.8 Å)