Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule
Open accessPublished version of a preprint
Abstract
ISRIB mechanism of action: In rodents, a druglike small molecule named ISRIB enhances cognition and reverses cognitive deficits after traumatic brain injury. ISRIB activates a protein complex called eIF2B that is required for the synthesis of new proteins. Tsai et al. report the visualization of eIF2B bound to ISRIB at near-atomic resolution by cryo–electron microscopy. Biochemical studies revealed that ISRIB is a “molecular staple” that promotes assembly of the fully active form of eIF2B. Zyryanova et al. report similar structures together with information on the binding of ISRIB analogs and their effects on protein translation. Science , this issue p. eaaq0939 , p. 1533
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Retrospective studies of MGs have shown their power in inactivating enzymes, potentiating enzymatic activities, blocking protein-protein interaction, modulating client proteins, and modifying splicing.
“Outside targeted protein degradation, retrospective studies of MGs have begun to showcase their versatile and promising power in inactivating enzymes by stabilizing autoinhibitory inter-domain interactions47, potentiating enzymatic activities by promoting protein oligomerization48,49, blocking protein–protein interaction by inducing unnatural homodimerization50, modulating the functions of client”
From Defining molecular glues with a dual-nanobody cannabidiol sensor (2022) · cites this paper as [48]
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References 49 · Cited by 192
Research works printed but not linked: 1
- [21]Harding HP, Ron D, in Translational Control in Biology and Medicine, Mathews MB, Sonenberg N, Hershey JWB, Eds. (Cold Spring Harbor, NY, 2007), pp. 345– 368.
- Authors
- Tsai, J. C., Miller-Vedam, L. E., Anand, A. A., Jaishankar, P., Nguyen, H. C., Renslo, A. R., Frost, A., & Walter, P.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of California, San Francisco (US)
- Corresponding author
- Frost, Adam
- Walter, Peter
- ORCID
- Venue
- Science
- Published
- 2018-03-30
- Volume
- 359
- Issue
- 6383
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6120582
- OpenAlex
- W2775790403
- Cited by
- 192
- References
- 49
- Citations by year
- 2026: 16 · 2025: 22 · 2024: 14 · 2023: 25 · 2022: 14 · 2021: 24 · 2020: 33 · 2019: 28 · 2018: 15
- FWCI
- 8.98
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute (Faculty Scholar 55108523)
- American Asthma Foundation (A127383)
- NIH (1DP2GM110772-01)
- Calico Life Sciences LLC
- Rogers Family Foundation
- Weill Foundation
- Searle Scholars Program
- Chan Zuckerberg Biohub
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- eIF2B, ISRIB, integrated stress response, eIF2α phosphorylation, guanine nucleotide exchange factor, protein complex structure, translational regulation, cognitive enhancement, brain injury
- MeSH terms
- Acetamides, Cyclohexylamines, Escherichia coli, Humans, Memory, Mutation, Phosphorylation, Protein Conformation, Recombinant Proteins, Protein Folding, Nootropic Agents, Cryoelectron Microscopy, Eukaryotic Initiation Factor-2B, Protein Multimerization, Protein Stability
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