• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

底物相互作用抑制 γ-分泌酶产生淀粉样β肽。

Substrate interaction inhibits γ-secretase production of amyloid-β peptides.

机构信息

Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.

Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

出版信息

Chem Commun (Camb). 2020 Feb 27;56(17):2578-2581. doi: 10.1039/c9cc09170j.

DOI:10.1039/c9cc09170j
PMID:32016207
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8219260/
Abstract

Combining NMR, mass spectrometry, AlphaLISA and cell assays, we discovered a compound C1 that binds C-terminal juxtamembrane lysines at the transmembrane domain of the amyloid precursor protein (APPTM) and inhibits γ-secretase production of amyloid-β with μM IC50. Our work suggests that targeting APPTM is a novel and viable strategy in AD drug discovery.

摘要

通过结合 NMR、质谱、AlphaLISA 和细胞检测，我们发现了一种名为 C1 的化合物，它可以结合淀粉样前体蛋白（APPTM）跨膜域的 C 端临近膜赖氨酸，以 μM 的 IC50 抑制 γ-分泌酶生成淀粉样-β。我们的工作表明，靶向 APPTM 是 AD 药物发现中的一种新颖且可行的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79b5/8219260/704ae1911678/nihms-1676708-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79b5/8219260/7bd7ff968203/nihms-1676708-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79b5/8219260/803209c2cfd6/nihms-1676708-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79b5/8219260/f8159b0c6e08/nihms-1676708-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79b5/8219260/0c7d45f7fbb1/nihms-1676708-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79b5/8219260/704ae1911678/nihms-1676708-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79b5/8219260/7bd7ff968203/nihms-1676708-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79b5/8219260/803209c2cfd6/nihms-1676708-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79b5/8219260/f8159b0c6e08/nihms-1676708-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79b5/8219260/0c7d45f7fbb1/nihms-1676708-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79b5/8219260/704ae1911678/nihms-1676708-f0005.jpg

相似文献

1
Substrate interaction inhibits γ-secretase production of amyloid-β peptides.底物相互作用抑制 γ-分泌酶产生淀粉样β肽。
Chem Commun (Camb). 2020 Feb 27;56(17):2578-2581. doi: 10.1039/c9cc09170j.
2
Identification of new Presenilin-1 phosphosites: implication for γ-secretase activity and Aβ production.新的早老素-1磷酸化位点的鉴定：对γ-分泌酶活性和Aβ生成的影响。
J Neurochem. 2015 May;133(3):409-21. doi: 10.1111/jnc.12996. Epub 2015 Feb 24.
3
Verteporfin is a substrate-selective γ-secretase inhibitor that binds the amyloid precursor protein transmembrane domain.维替泊芬是一种底物选择性 γ-分泌酶抑制剂，可与淀粉样前体蛋白跨膜结构域结合。
J Biol Chem. 2022 Apr;298(4):101792. doi: 10.1016/j.jbc.2022.101792. Epub 2022 Mar 3.
4
Expression, purification, and reconstitution of the transmembrane domain of the human amyloid precursor protein for NMR studies.用于核磁共振研究的人淀粉样前体蛋白跨膜结构域的表达、纯化及重组
Protein Expr Purif. 2012 Jan;81(1):11-17. doi: 10.1016/j.pep.2011.08.006. Epub 2011 Aug 31.
5
Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by γ-Secretase and Amyloid-β Peptide Production.锌和铜对γ-分泌酶处理淀粉样前体蛋白及淀粉样β肽生成的调节作用存在差异。
J Biol Chem. 2017 Mar 3;292(9):3751-3767. doi: 10.1074/jbc.M116.754101. Epub 2017 Jan 17.
6
[Expression, purification and micelle reconstruction of the transmembrane domain of the human amyloid precursor protein for NMR studies].[用于核磁共振研究的人淀粉样前体蛋白跨膜结构域的表达、纯化及胶束重建]
Sheng Wu Gong Cheng Xue Bao. 2023 Apr 25;39(4):1633-1643. doi: 10.13345/j.cjb.220786.
7
Retention in endoplasmic reticulum 1 (RER1) modulates amyloid-β (Aβ) production by altering trafficking of γ-secretase and amyloid precursor protein (APP).内质网 1（RER1）的保留通过改变 γ-分泌酶和淀粉样前体蛋白（APP）的运输来调节淀粉样β（Aβ）的产生。
J Biol Chem. 2012 Nov 23;287(48):40629-40. doi: 10.1074/jbc.M112.418442. Epub 2012 Oct 5.
8
Influence of the familial Alzheimer's disease-associated T43I mutation on the transmembrane structure and γ-secretase processing of the C99 peptide.家族性阿尔茨海默病相关 T43I 突变对 C99 肽跨膜结构和 γ-分泌酶加工的影响。
J Biol Chem. 2019 Apr 12;294(15):5854-5866. doi: 10.1074/jbc.RA118.006061. Epub 2019 Feb 12.
9
Combining an amyloid-beta (Aβ) cleaving enzyme inhibitor with a γ-secretase modulator results in an additive reduction of Aβ production.联合使用淀粉样蛋白-β（Aβ）裂解酶抑制剂和 γ-分泌酶调节剂可使 Aβ 产生量得到附加减少。
FEBS J. 2015 Jan;282(1):65-73. doi: 10.1111/febs.13103. Epub 2014 Nov 7.
10
Lysine 624 of the amyloid precursor protein (APP) is a critical determinant of amyloid β peptide length: support for a sequential model of γ-secretase intramembrane proteolysis and regulation by the amyloid β precursor protein (APP) juxtamembrane region.淀粉样前体蛋白（APP）的赖氨酸 624 是淀粉样 β 肽长度的关键决定因素：支持 γ-分泌酶跨膜蛋白水解的顺序模型和淀粉样 β 前体蛋白（APP）近膜区的调节。
J Biol Chem. 2011 Nov 18;286(46):39804-12. doi: 10.1074/jbc.M111.274696. Epub 2011 Aug 25.

引用本文的文献

1
Specific Mutations near the Amyloid Precursor Protein Cleavage Site Increase γ-Secretase Sensitivity and Modulate Amyloid-β Production.淀粉样前体蛋白裂解位点附近的特定突变增加 γ-分泌酶敏感性并调节淀粉样β生成。
Int J Mol Sci. 2023 Feb 16;24(4):3970. doi: 10.3390/ijms24043970.
2
Covalent fragment inhibits intramembrane proteolysis.共价片段抑制膜内蛋白水解。
Front Mol Biosci. 2022 Sep 7;9:958399. doi: 10.3389/fmolb.2022.958399. eCollection 2022.
3
Targeting Amyloidogenic Processing of APP in Alzheimer's Disease.针对阿尔茨海默病中淀粉样前体蛋白的淀粉样生成加工过程

本文引用的文献

1
Recognition of the amyloid precursor protein by human γ-secretase.人γ-分泌酶对淀粉样前体蛋白的识别。
Science. 2019 Feb 15;363(6428). doi: 10.1126/science.aaw0930. Epub 2019 Jan 10.
2
Coupled Transmembrane Substrate Docking and Helical Unwinding in Intramembrane Proteolysis of Amyloid Precursor Protein.跨膜底物对接与淀粉样前体蛋白跨膜水解过程中的螺旋解旋
Sci Rep. 2018 Aug 17;8(1):12411. doi: 10.1038/s41598-018-30015-6.
3
Bexarotene Binds to the Amyloid Precursor Protein Transmembrane Domain, Alters Its α-Helical Conformation, and Inhibits γ-Secretase Nonselectively in Liposomes.
Front Mol Neurosci. 2020 Aug 4;13:137. doi: 10.3389/fnmol.2020.00137. eCollection 2020.
倍他罗汀与淀粉样前体蛋白跨膜结构域结合，改变其α-螺旋构象，并在脂质体中非选择性抑制γ-分泌酶。
ACS Chem Neurosci. 2018 Jul 18;9(7):1702-1713. doi: 10.1021/acschemneuro.8b00068. Epub 2018 May 11.
4
Down Syndrome, Partial Trisomy 21, and Absence of Alzheimer's Disease: The Role of APP.唐氏综合征、21号染色体部分三体与阿尔茨海默病的缺失：淀粉样前体蛋白（APP）的作用
J Alzheimers Dis. 2017;56(2):459-470. doi: 10.3233/JAD-160836.
5
The amyloid hypothesis of Alzheimer's disease at 25 years.阿尔茨海默病淀粉样蛋白假说25年回顾
EMBO Mol Med. 2016 Jun 1;8(6):595-608. doi: 10.15252/emmm.201606210. Print 2016 Jun.
6
Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH.古细菌早老素同源物PSH对淀粉样前体蛋白的切割
Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3344-9. doi: 10.1073/pnas.1502150112. Epub 2015 Mar 2.
7
Alzheimer's Disease in Down Syndrome.唐氏综合征中的阿尔茨海默病
Eur J Neurodegener Dis. 2012 Dec;1(3):353-364.
8
Familial Alzheimer's mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site.淀粉样前体蛋白跨膜区（APPTM）内的家族性阿尔茨海默病突变通过增强ε-切割位点的可及性来增加Aβ42的产生。
Nat Commun. 2014;5:3037. doi: 10.1038/ncomms4037.
9
Substrate ectodomain is critical for substrate preference and inhibition of γ-secretase.底物外结构域对于底物偏好性和 γ-分泌酶的抑制至关重要。
Nat Commun. 2013;4:2529. doi: 10.1038/ncomms3529.
10
Structure of a presenilin family intramembrane aspartate protease.早老素家族跨膜天冬氨酸蛋白酶结构域。
Nature. 2013 Jan 3;493(7430):56-61. doi: 10.1038/nature11801. Epub 2012 Dec 19.