7pw5
Human SMG1-8-9 kinase complex with AlphaFold predicted SMG8 C-terminus, bound to a SMG1 inhibitor
Structural highlights
DiseaseSMG9_HUMAN The disease is caused by mutations affecting the gene represented in this entry. FunctionSMG9_HUMAN Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons (PubMed:19417104). Is recruited by release factors to stalled ribosomes together with SMG1 and SMG8 (forming the SMG1C protein kinase complex) and, in the SMG1C complex, is required for the efficient association between SMG1 and SMG8 (PubMed:19417104). Plays a role in brain, heart, and eye development (By similarity).[UniProtKB:Q9DB90][1] Publication Abstract from PubMedThe PI3K-related kinase (PIKK) SMG1 monitors the progression of metazoan nonsense-mediated mRNA decay (NMD) by phosphorylating the RNA helicase UPF1. Previous work has shown that the activity of SMG1 is impaired by small molecule inhibitors, is reduced by the SMG1 interactors SMG8 and SMG9, and is downregulated by the so-called SMG1 insertion domain. However, the molecular basis for this complex regulatory network has remained elusive. Here, we present cryo-electron microscopy reconstructions of human SMG1-9 and SMG1-8-9 complexes bound to either a SMG1 inhibitor or a non-hydrolyzable ATP analog at overall resolutions ranging from 2.8 to 3.6 A. These structures reveal the basis with which a small molecule inhibitor preferentially targets SMG1 over other PIKKs. By comparison with our previously reported substrate-bound structure (Langer et al.,2020), we show that the SMG1 insertion domain can exert an autoinhibitory function by directly blocking the substrate-binding path as well as overall access to the SMG1 kinase active site. Together with biochemical analysis, our data indicate that SMG1 autoinhibition is stabilized by the presence of SMG8. Our results explain the specific inhibition of SMG1 by an ATP-competitive small molecule, provide insights into regulation of its kinase activity within the NMD pathway, and expand the understanding of PIKK regulatory mechanisms in general. Cryo-EM reconstructions of inhibitor-bound SMG1 kinase reveal an autoinhibitory state dependent on SMG8.,Langer LM, Bonneau F, Gat Y, Conti E Elife. 2021 Oct 26;10. pii: 72353. doi: 10.7554/eLife.72353. PMID:34698635[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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