7d44

From Proteopedia

eIF2B-eIF2(aP), aP2 complex

Structural highlights

7d44 is a 12 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 4Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

EI2BA_HUMAN Cree leukoencephalopathy;Late infantile CACH syndrome;Ovarioleukodystrophy. The disease is caused by mutations affecting the gene represented in this entry.

Function

EI2BA_HUMAN Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP.

Publication Abstract from PubMed

The small molecule ISRIB antagonizes the activation of the integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(alphaP). ISRIB and eIF2(alphaP) 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(alphaP) and is attenuated by mutations that desensitize eIF2B to the inhibitory effect of eIF2(alphaP). ISRIB's efficacy as an ISR inhibitor in cells also depends on presence of eIF2(alphaP). Cryoelectron microscopy (cryo-EM) showed that engagement of both eIF2B regulatory sites by two eIF2(alphaP) molecules remodels both the ISRIB-binding pocket and the pockets that would engage eIF2alpha during active nucleotide exchange, thereby discouraging both binding events. In vitro, eIF2(alphaP) 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.

ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B.,Zyryanova AF, Kashiwagi K, Rato C, Harding HP, Crespillo-Casado A, Perera LA, Sakamoto A, Nishimoto M, Yonemochi M, Shirouzu M, Ito T, Ron D Mol Cell. 2021 Jan 7;81(1):88-103.e6. doi: 10.1016/j.molcel.2020.10.031. Epub , 2020 Nov 20. PMID:33220178^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zyryanova AF, Kashiwagi K, Rato C, Harding HP, Crespillo-Casado A, Perera LA, Sakamoto A, Nishimoto M, Yonemochi M, Shirouzu M, Ito T, Ron D. ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B. Mol Cell. 2021 Jan 7;81(1):88-103.e6. PMID:33220178 doi:10.1016/j.molcel.2020.10.031