Evidence map›Paper›PMID 26586190›Full record

ArticleScience (New York, N.Y.)2016

Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway.

Robert A Saxton, Kevin E Knockenhauer, Rachel L Wolfson, Lynne Chantranupong, Michael E Pacold, Tim Wang, Thomas U Schwartz, David M Sabatini

Registry-linked trialOpen access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Science (New York, N.Y.), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT07586891 (A Randomized, Double-Blind, Single-Center, Exploratory Study With Parallel Controls on the Safety and Efficacy of Neoadjuvant Low Branched-Chain Amino Acid Diet in Combination With Anti-PD-1 Monoclonal Antibody for Stage III Melanoma), which is not on this map. Cited by 275 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
275citing papers in PubMed, 1 pooled it
17.0field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT07586891 narecruitingnot on this mapstarted 2024, after this paper: background citation

A Randomized, Double-Blind, Single-Center, Exploratory Study With Parallel Controls on the Safety and Efficacy of Neoadjuvant Low Branched-Chain Amino Acid Diet in Combination With Anti-PD-1 Monoclonal Antibody for Stage III Melanoma

TypeinterventionalSponsorXijing HospitalRan2024 to 2027Enrolled80ConditionsMelanoma (Skin Cancer)ArmsLow Branched-Chain Amino Acid Diet
3 · Its place in the literature

Who cites it

275 citing papers in PubMed, 1 synthesis or guideline pooled it, 438 citations in OpenAlex.

  1. Pooled it
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  15. Frontiers in microbiology · 2026
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215 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

8 authors at 3 institutions in 1 country.

Robert A SaxtonDepartment of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA.
Kevin E KnockenhauerDepartment of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
Rachel L WolfsonDepartment of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA.
Lynne ChantranupongDepartment of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA.
Michael E PacoldDepartment of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA.
Tim WangDepartment of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA.
Thomas U SchwartzDepartment of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
David M SabatiniDepartment of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA. sabatini@wi.mit.edu.
Massachusetts Institute of Technology · USBroad Institute · USHoward Hughes Medical Institute · US

Funding

VIRUS PRODUCTION COREP30CA014051 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI Jacqueline A. Lees · 1985 to 2026
$93.9M
Medical Scientist Training ProgramT32GM007753 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI WALENSKY, LOREN DAVID · 1985 to 2021
$50.0M
PRE-DOCTORAL TRAINING IN THE BIOLOGICAL SCIENCEST32GM007287 · NIGMS · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI BELL, STEPHEN P., KEATING, AMY E · 1985 to 2019
$40.8M
Overall EvaluationP41GM103403 · NIGMS · CORNELL UNIVERSITY · PI EALICK, STEVEN E · 2012 to 2017
$14.3M
Regulation of the mTOR Pathway By NutrientsR01CA103866 · NCI · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · PI WEISSMAN, JONATHAN S. · 2004 to 2021
$7.0M
TRANSLATIONAL CONTROL BY RAPAMYCIN-SENSITIVE SIGNALINGR01AI047389 · NIAID · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · PI WEISSMAN, JONATHAN S. · 2000 to 2021
$4.9M
Novel Components of the mTORC1 and mTORC2 PathwaysR37AI047389 · NIAID · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · PI SABATINI, DAVID M. · 2010 to 2019
$4.8M
Pixel Array Detector for X-ray CrystallographyS10RR029205 · NCRR · CORNELL UNIVERSITY · PI EALICK, STEVEN E · 2010 to 2010
$1.8M
Characterization of GATOR1 signaling to mTORC1 and its role in cancerF30CA189333 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI WOLFSON, RACHEL LAURA · 2015 to 2017
$146k
Characterization of MWS/DEN, a novel regulator of amino acid signaling to mTORC1F31CA180271 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI CHANTRANUPONG, LYNNE · 2013 to 2015
$128k
Improving targeted therapies through functional genomic approachesF31CA189437 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI WANG, TIM · 2014 to 2017
$107k
Howard Hughes Medical InstituteNCI NIH HHS F30 CA189333NCI NIH HHS F31 CA180271NCI NIH HHS F31 CA189437NCI NIH HHS P30 CA014051NCI NIH HHS R01 CA103866NCI NIH HHS R01CA103866NCRR NIH HHS S10 RR029205NIAID NIH HHS AI47389NIAID NIH HHS R01 AI047389NIAID NIH HHS R37 AI047389NIGMS NIH HHS P41 GM103403NIGMS NIH HHS T32 GM007287NIGMS NIH HHS T32GM007287NIGMS NIH HHS T32 GM007753
6 · The paper itself

Abstract

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.

Indexed as

Amino Acid SequenceBinding SitesCrystallography, X-RayHEK293 CellsHumansLeucineMechanistic Target of Rapamycin Complex 1Metabolic Networks and PathwaysMolecular Sequence DataMultiprotein ComplexesMutationNuclear ProteinsProtein BindingProtein Structure, SecondaryProtein Structure, TertiarySestrinsLeucineMechanistic Target of Rapamycin Complex 1Multiprotein ComplexesNuclear ProteinsSESN2 protein, humanSestrinsTOR Serine-Threonine Kinases

Identifiers

PMID26586190
PMCPMC4698039
OpenAlexW2231368253

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.