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DOI | 10.1126/science.aaq0939 |
Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule | |
Tsai, Jordan C.1,2; Miller-Vedam, Lakshmi E.2,3; Anand, Aditya A.1,2; Jaishankar, Priyadarshini4,5; Nguyen, Henry C.2,3; Renslo, Adam R.4,5; Frost, Adam2,3; Walter, Peter1,2 | |
2018-03-30 | |
发表期刊 | SCIENCE
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ISSN | 0036-8075 |
EISSN | 1095-9203 |
出版年 | 2018 |
卷号 | 359期号:6383页码:1483-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA |
英文摘要 | Regulation by the integrated stress response (ISR) converges on the phosphorylation of translation initiation factor eIF2 in response to a variety of stresses. Phosphorylation converts eIF2 from a substrate to a competitive inhibitor of its dedicated guanine nucleotide exchange factor, eIF2B, thereby inhibiting translation. ISRIB, a drug-like eIF2B activator, reverses the effects of eIF2 phosphorylation, and in rodents it enhances cognition and corrects cognitive deficits after brain injury. To determine its mechanism of action, we solved an atomic-resolution structure of ISRIB bound in a deep cleft within decameric human eIF2B by cryo-electron microscopy. Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of two identical tetrameric subcomplexes, and ISRIB promoted this step by cross-bridging a central symmetry interface. Thus, regulation of eIF2B assembly emerges as a rheostat for eIF2B activity that tunes translation during the ISR and that can be further modulated by ISRIB. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000428657000036 |
WOS关键词 | INITIATION-FACTOR EIF2B ; ALPHA-SUBUNIT ; REGULATORY SUBCOMPLEX ; TRANSLATIONAL CONTROL ; CRYSTAL-STRUCTURE ; INHIBITION ; ARCHITECTURE ; EIF2-ALPHA ; INSIGHTS ; COMPLEX |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/198296 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA; 2.Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA; 3.Chan Zuckerberg Biohub, San Francisco, CA 94158 USA; 4.Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA USA; 5.Univ Calif San Francisco, Small Mol Discovery Ctr, San Francisco, CA 94143 USA |
推荐引用方式 GB/T 7714 | Tsai, Jordan C.,Miller-Vedam, Lakshmi E.,Anand, Aditya A.,et al. Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule[J]. SCIENCE,2018,359(6383):1483-+. |
APA | Tsai, Jordan C..,Miller-Vedam, Lakshmi E..,Anand, Aditya A..,Jaishankar, Priyadarshini.,Nguyen, Henry C..,...&Walter, Peter.(2018).Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule.SCIENCE,359(6383),1483-+. |
MLA | Tsai, Jordan C.,et al."Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule".SCIENCE 359.6383(2018):1483-+. |
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