6N0M

CRYSTAL STRUCTURE OF SESTRIN2 IN COMPLEX WITH NV-0005138

6N0M の概要

• エントリーDOI: 10.2210/pdb6n0m/pdb
• 分子名称: Sestrin-2, 4-(difluoromethyl)-L-leucine (2 entities in total)
• 機能のキーワード: mtor, leucine, amino-acid, sensing, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 238199.55

構造登録者

O'Neill, D. (登録日: 2018-11-07, 公開日: 2019-04-10, 最終更新日: 2023-10-11)

主引用文献

Sengupta, S.,Giaime, E.,Narayan, S.,Hahm, S.,Howell, J.,O'Neill, D.,Vlasuk, G.P.,Saiah, E.
Discovery of NV-5138, the first selective Brain mTORC1 activator.
Sci Rep, 9:4107-4107, 2019

PubMed Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) has been linked to several important chronic medical conditions many of which are associated with advancing age. A variety of inputs including the amino acid leucine are required for full mTORC1 activation. The cytoplasmic proteins Sestrin1 and Sestrin2 specifically bind to the multiprotein complex GATOR2 and communicate leucine sufficiency to the mTORC1 pathway activation complex. Herein, we report NV-5138, a novel orally bioavailable compound that binds to Sestrin2 and activates mTORC1 both in vitro and in vivo. NV-5138 like leucine transiently activates mTORC1 in several peripheral tissues, but in contrast to leucine uniquely activates this complex in the brain due lack of metabolism and utilization in protein synthesis. As such, NV-5138 will permit the exploration in areas of unmet medical need including neuropsychiatric conditions and cognition which have been linked to the activation status of mTORC1.

PubMed: 30858438
DOI: 10.1038/s41598-019-40693-5

実験手法

X-RAY DIFFRACTION (3.3 Å)