التفاصيل البيبلوغرافية
| العنوان: |
Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM |
| المؤلفون: |
Hanwen Zhu, Patricia Hixson, Wen Ma, Ji Sun |
| المصدر: |
Cell Discovery, Vol 10, Iss 1, Pp 1-12 (2024) |
| بيانات النشر: |
Nature Publishing Group, 2024. |
| سنة النشر: |
2024 |
| المجموعة: |
LCC:Cytology |
| مصطلحات موضوعية: |
Cytology, QH573-671 |
| الوصف: |
Abstract LRRK2 is one of the most promising drug targets for Parkinson’s disease. Though type I kinase inhibitors of LRRK2 are under clinical trials, alternative strategies like type II inhibitors are being actively pursued due to the potential undesired effects of type I inhibitors. Currently, a robust method for LRRK2–inhibitor structure determination to guide structure-based drug discovery is lacking, and inhibition mechanisms of available compounds are also unclear. Here we present near-atomic-resolution structures of LRRK2 with type I (LRRK2-IN-1 and GNE-7915) and type II (rebastinib, ponatinib, and GZD-824) inhibitors, uncovering the structural basis of LRRK2 inhibition and conformational plasticity of the kinase domain with molecular dynamics (MD) simulations. Type I and II inhibitors bind to LRRK2 in active-like and inactive conformations, so LRRK2–inhibitor complexes further reveal general structural features associated with LRRK2 activation. Our study provides atomic details of LRRK2–inhibitor interactions and a framework for understanding LRRK2 activation and for rational drug design. |
| نوع الوثيقة: |
article |
| وصف الملف: |
electronic resource |
| اللغة: |
English |
| تدمد: |
2056-5968 |
| Relation: |
https://doaj.org/toc/2056-5968 |
| DOI: |
10.1038/s41421-023-00639-8 |
| URL الوصول: |
https://doaj.org/article/00f58e1f35a8408f9573a5fa7ef77026 |
| رقم الانضمام: |
edsdoj.00f58e1f35a8408f9573a5fa7ef77026 |
| قاعدة البيانات: |
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