5MLE

Crystal Structure of Human Dihydropyrimidinease-like 2 (DPYSL2A)/Collapsin Response Mediator Protein (CRMP2 13-516) Mutant Y479E/Y499E

5MLE の概要

• エントリーDOI: 10.2210/pdb5mle/pdb
• 分子名称: Dihydropyrimidinase-related protein 2, DI(HYDROXYETHYL)ETHER, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: crmp2, phospho-mutant, ovarian cancer, microtubule associated protein, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 111128.50

構造登録者

Sethi, R.,Zheng, Y.,Talon, R.,Velupillai, S.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Ahmed, A.A.,von Delft, F. (登録日: 2016-12-06, 公開日: 2017-02-22, 最終更新日: 2024-01-17)

主引用文献

Zheng, Y.,Sethi, R.,Mangala, L.S.,Taylor, C.,Goldsmith, J.,Wang, M.,Masuda, K.,Karaminejadranjbar, M.,Mannion, D.,Miranda, F.,Herrero-Gonzalez, S.,Hellner, K.,Chen, F.,Alsaadi, A.,Albukhari, A.,Fotso, D.C.,Yau, C.,Jiang, D.,Pradeep, S.,Rodriguez-Aguayo, C.,Lopez-Berestein, G.,Knapp, S.,Gray, N.S.,Campo, L.,Myers, K.A.,Dhar, S.,Ferguson, D.,Bast, R.C.,Sood, A.K.,von Delft, F.,Ahmed, A.A.
Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation.
Nat Commun, 9:476-476, 2018

PubMed Abstract: Though used widely in cancer therapy, paclitaxel only elicits a response in a fraction of patients. A strong determinant of paclitaxel tumor response is the state of microtubule dynamic instability. However, whether the manipulation of this physiological process can be controlled to enhance paclitaxel response has not been tested. Here, we show a previously unrecognized role of the microtubule-associated protein CRMP2 in inducing microtubule bundling through its carboxy terminus. This activity is significantly decreased when the FER tyrosine kinase phosphorylates CRMP2 at Y479 and Y499. The crystal structures of wild-type CRMP2 and CRMP2-Y479E reveal how mimicking phosphorylation prevents tetramerization of CRMP2. Depletion of FER or reducing its catalytic activity using sub-therapeutic doses of inhibitors increases paclitaxel-induced microtubule stability and cytotoxicity in ovarian cancer cells and in vivo. This work provides a rationale for inhibiting FER-mediated CRMP2 phosphorylation to enhance paclitaxel on-target activity for cancer therapy.

PubMed: 29396402
DOI: 10.1038/s41467-017-02811-7

実験手法

X-RAY DIFFRACTION (2.48 Å)