6N0M
CRYSTAL STRUCTURE OF SESTRIN2 IN COMPLEX WITH NV-0005138
Summary for 6N0M
| Entry DOI | 10.2210/pdb6n0m/pdb |
| Descriptor | Sestrin-2, 4-(difluoromethyl)-L-leucine (2 entities in total) |
| Functional Keywords | mtor, leucine, amino-acid, sensing, signaling protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 5 |
| Total formula weight | 238199.55 |
| Authors | O'Neill, D. (deposition date: 2018-11-07, release date: 2019-04-10, Last modification date: 2023-10-11) |
| Primary citation | 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 Cited by 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: 30858438DOI: 10.1038/s41598-019-40693-5 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.3 Å) |
Structure validation
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