Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Cryo-EM reconstructions of inhibitor-bound SMG1 kinase reveal an autoinhibitory state dependent on SMG8.
Journal, issue, pages	Elife, Vol. 10, Year 2021
Publish date	Oct 26, 2021
Authors	Lukas M Langer / Fabien Bonneau / Yair Gat / Elena Conti /
PubMed Abstract	The 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 ...The 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 Å. 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.
External links	Elife / PubMed:34698635 / PubMed Central
Methods	EM (single particle)
Resolution	2.82 - 3.59 Å
Structure data	13674 7pw4 EMDB-13674, PDB-7pw4: Human SMG1-8-9 kinase complex bound to a SMG1 inhibitor Method: EM (single particle) / Resolution: 3.27 Å 13675 7pw5 EMDB-13675, PDB-7pw5: Human SMG1-8-9 kinase complex with AlphaFold predicted SMG8 C-terminus, bound to a SMG1 inhibitor Method: EM (single particle) / Resolution: 3.4 Å 13676 7pw6 EMDB-13676, PDB-7pw6: Human SMG1-8-9 kinase complex bound to a SMG1 inhibitor - SMG1 body Method: EM (single particle) / Resolution: 3.05 Å 13677 7pw7 EMDB-13677, PDB-7pw7: Human SMG1-9 kinase complex bound to a SMG1 inhibitor Method: EM (single particle) / Resolution: 3.59 Å 13678 7pw8 EMDB-13678, PDB-7pw8: Human SMG1-8-9 kinase complex bound to AMPPNP Method: EM (single particle) / Resolution: 2.82 Å 13679 7pw9 EMDB-13679, PDB-7pw9: Human SMG1-9 kinase complex bound to AMPPNP Method: EM (single particle) / Resolution: 3.12 Å
Chemicals	ChemComp-IHP: INOSITOL HEXAKISPHOSPHATE ChemComp-88C: 1-[4-[4-[2-[[4-chloranyl-3-(diethylsulfamoyl)phenyl]amino]pyrimidin-4-yl]pyridin-2-yl]phenyl]-3-methyl-urea ChemComp-ATP: ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying moleculeYM ChemComp-MG: Unknown entry ChemComp-ANP: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogueYM
Source	homo sapiens (human)
Keywords	TRANSFERASE / Complex