期刊
SCIENCE
卷 351, 期 6268, 页码 53-58出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aad2087
关键词
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资金
- Navitor Pharmaceuticals
- National Institute of General Medical Sciences from the National Institutes of Health [P41 GM103403]
- NIH-ORIP HEI grant [S10 RR029205]
- DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
- NIH [T32GM007287, R01CA103866, AI47389, T32 GM007753, F30 CA189333, F31 CA180271, F31 CA189437]
- U.S. Department of Defense [W81XWH-07-0448]
- MIT Whitaker Health Sciences Fund
- Sally Gordon Fellowship of the Damon Runyon Cancer Research Foundation [DRG-112-12]
- Department of Defense Breast Cancer Research Program Postdoctoral Fellowship [BC120208]
- NATIONAL CANCER INSTITUTE [P30CA014051, F31CA180271, F30CA189333, F31CA189437, R01CA103866] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR029205] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R37AI047389, R01AI047389] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007287, P41GM103403, T32GM007753] Funding Source: NIH RePORTER
Eukaryotic cells coordinate growth with the availability of nutrients through the mechanistic target of rapamycin complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag guanosine triphosphatases and their regulators GATOR1 and GATOR2. Sestrin2 interacts with GATOR2 and is a leucine sensor. Here we present the 2.7 angstrom crystal structure of Sestrin2 in complex with leucine. Leucine binds through a single pocket that coordinates its charged functional groups and confers specificity for the hydrophobic side chain. A loop encloses leucine and forms a lid-latch mechanism required for binding. A structure-guided mutation in Sestrin2 that decreases its affinity for leucine leads to a concomitant increase in the leucine concentration required for mTORC1 activation in cells. These results provide a structural mechanism of amino acid sensing by the mTORC1 pathway.
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