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ISRIB 通过别构拮抗磷酸化 eIF2 对 eIF2B 的抑制作用来削弱整体应激反应。

ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B.

机构信息

Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge CB2 0XY, UK.

RIKEN Center for Biosystems Dynamics Research, Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.

出版信息

Mol Cell. 2021 Jan 7;81(1):88-103.e6. doi: 10.1016/j.molcel.2020.10.031. Epub 2020 Nov 20.

DOI:10.1016/j.molcel.2020.10.031
PMID:33220178
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7837216/
Abstract

The small molecule ISRIB antagonizes the activation of the integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). ISRIB and eIF2(αP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange factor for eIF2. We have found that ISRIB-mediated acceleration of eIF2B's nucleotide exchange activity in vitro is observed preferentially in the presence of eIF2(αP) and is attenuated by mutations that desensitize eIF2B to the inhibitory effect of eIF2(αP). ISRIB's efficacy as an ISR inhibitor in cells also depends on presence of eIF2(αP). Cryoelectron microscopy (cryo-EM) showed that engagement of both eIF2B regulatory sites by two eIF2(αP) molecules remodels both the ISRIB-binding pocket and the pockets that would engage eIF2α during active nucleotide exchange, thereby discouraging both binding events. In vitro, eIF2(αP) and ISRIB reciprocally opposed each other's binding to eIF2B. These findings point to antagonistic allostery in ISRIB action on eIF2B, culminating in inhibition of the ISR.

摘要

小分子 ISRIB 通过磷酸化翻译起始因子 2(eIF2(αP))拮抗整合应激反应 (ISR) 的激活。ISRIB 和 eIF2(αP) 在它们的共同靶标 eIF2B 上结合不同的位点，eIF2B 是 eIF2 的鸟嘌呤核苷酸交换因子。我们发现，ISRIB 在体外介导的 eIF2B 核苷酸交换活性的加速优先发生在存在 eIF2(αP)的情况下，并且被突变削弱，这些突变使 eIF2B 对 eIF2(αP)的抑制作用脱敏。ISRIB 在细胞中作为 ISR 抑制剂的功效也取决于 eIF2(αP)的存在。冷冻电镜 (cryo-EM) 显示，两个 eIF2(αP)分子与 eIF2B 的两个调节位点结合，重塑了 ISRIB 结合口袋和在活性核苷酸交换过程中与 eIF2α 结合的口袋，从而阻止了这两个结合事件。在体外，eIF2(αP)和 ISRIB 相互拮抗彼此与 eIF2B 的结合。这些发现表明 ISRIB 对 eIF2B 的作用存在变构拮抗作用，最终导致 ISR 的抑制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/782a/7837216/3f076b0b3487/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/782a/7837216/9151eb72ef44/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/782a/7837216/063c3904fd7b/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/782a/7837216/4b2457995abe/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/782a/7837216/2a04bb2beea7/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/782a/7837216/e156dc751d26/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/782a/7837216/8c80feea26d6/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/782a/7837216/ae1be3393f22/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/782a/7837216/3f076b0b3487/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/782a/7837216/9151eb72ef44/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/782a/7837216/063c3904fd7b/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/782a/7837216/4b2457995abe/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/782a/7837216/2a04bb2beea7/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/782a/7837216/e156dc751d26/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/782a/7837216/8c80feea26d6/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/782a/7837216/ae1be3393f22/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/782a/7837216/3f076b0b3487/gr7.jpg

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