Fully activated structure of the sterol-bound Smoothened GPCR-Gi protein complex.
G protein–coupled receptor
Smoothened receptor
activation
molecular dynamics
sterols
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
05 Dec 2023
05 Dec 2023
Historique:
pmc-release:
28
05
2024
medline:
30
11
2023
pubmed:
28
11
2023
entrez:
28
11
2023
Statut:
ppublish
Résumé
Smoothened (SMO) is an oncoprotein and signal transducer in the Hedgehog signaling pathway that regulates cellular differentiation and embryogenesis. As a member of the Frizzled (Class F) family of G protein-coupled receptors (GPCRs), SMO biochemically and functionally interacts with Gi family proteins. However, key molecular features of fully activated, G protein-coupled SMO remain elusive. We present the atomistic structure of activated human SMO complexed with the heterotrimeric Gi protein and two sterol ligands, equilibrated at 310 K in a full lipid bilayer at physiological salt concentration and pH. In contrast to previous experimental structures, our equilibrated SMO complex exhibits complete breaking of the pi-cation interaction between R451
Identifiants
pubmed: 38015850
doi: 10.1073/pnas.2300919120
pmc: PMC10710022
doi:
Substances chimiques
Sterols
0
Ligands
0
Hedgehog Proteins
0
Receptors, G-Protein-Coupled
0
Smoothened Receptor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2300919120Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL155532
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL150807
Pays : United States
Déclaration de conflit d'intérêts
Competing interests statement:The authors declare no competing interest.
Références
Nature. 2013 May 16;497(7449):338-43
pubmed: 23636324
Nat Commun. 2014 Jul 10;5:4355
pubmed: 25008467
ACS Pharmacol Transl Sci. 2018 Jul 26;1(1):12-20
pubmed: 32219201
PLoS Genet. 2015 Aug 20;11(8):e1005473
pubmed: 26291458
Nat Commun. 2019 Feb 8;10(1):667
pubmed: 30737406
Trends Pharmacol Sci. 2016 Jan;37(1):62-72
pubmed: 26432668
Nat Commun. 2014;5:3309
pubmed: 24525480
Elife. 2013 Oct 29;2:e01340
pubmed: 24171105
Nature. 2016 Jul 28;535(7613):517-522
pubmed: 27437577
Nature. 2021 Jun;594(7864):594-598
pubmed: 33911284
J Chem Theory Comput. 2008 Dec 9;4(12):2160-9
pubmed: 26620487
Sci Adv. 2022 Jun 3;8(22):eabm5563
pubmed: 35658032
Cell. 2018 Jul 12;174(2):312-324.e16
pubmed: 29804838
Structure. 2019 Mar 5;27(3):549-559.e2
pubmed: 30595453
Biophys J. 2016 Jun 21;110(12):2618-2629
pubmed: 27332120
Nat Chem Biol. 2020 Dec;16(12):1368-1375
pubmed: 32929279
Cell. 2012 Sep 28;151(1):14-23
pubmed: 23021212
Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):E11141-E11150
pubmed: 29229834
Nat Struct Mol Biol. 2021 Nov;28(11):879-888
pubmed: 34759375
Nat Chem. 2023 Aug;15(8):1127-1137
pubmed: 37349378
Nat Chem Biol. 2012 Jan 08;8(2):211-20
pubmed: 22231273
Nat Commun. 2017 May 17;8:15383
pubmed: 28513578
Cell Rep. 2017 Jun 6;19(10):2074-2087
pubmed: 28591579
Dev Cell. 2013 Aug 26;26(4):346-57
pubmed: 23954590
Dev Cell. 2016 Aug 22;38(4):333-44
pubmed: 27554855
Cell Chem Biol. 2017 Mar 16;24(3):252-280
pubmed: 28286127
Nat Commun. 2023 Feb 13;14(1):794
pubmed: 36781870
Nature. 2019 Jul;571(7764):279-283
pubmed: 31168089
Proc Natl Acad Sci U S A. 2022 May 3;119(18):e2110085119
pubmed: 35452328
Curr Opin Struct Biol. 2008 Dec;18(6):734-40
pubmed: 18957321
Cell. 2016 Aug 25;166(5):1176-1187.e14
pubmed: 27545348
Nature. 2019 Jul;571(7764):284-288
pubmed: 31263273
Biochim Biophys Acta Biomembr. 2022 Aug 1;1864(8):183946
pubmed: 35483421
Proc Natl Acad Sci U S A. 2020 Mar 17;117(11):5836-5843
pubmed: 32127473
Nat Commun. 2022 Jul 28;13(1):4366
pubmed: 35902590
Development. 2019 May 15;146(10):
pubmed: 31092502
Biophys J. 2023 Apr 4;122(7):1400-1413
pubmed: 36883002
Nat Chem Biol. 2013 Sep;9(9):557-64
pubmed: 23831757
Nat Methods. 2017 Jan;14(1):71-73
pubmed: 27819658