Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-α-MSH and setmelanotide.
Journal
Cell research
ISSN: 1748-7838
Titre abrégé: Cell Res
Pays: England
ID NLM: 9425763
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
08
05
2021
accepted:
31
08
2021
pubmed:
26
9
2021
medline:
27
1
2022
entrez:
25
9
2021
Statut:
ppublish
Résumé
The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of obesity. Here, we present cryo-electron microscopy structures of MC4R-Gs-protein complexes with two drugs recently approved by the FDA, the peptide agonists NDP-α-MSH and setmelanotide, with 2.9 Å and 2.6 Å resolution. Together with signaling data from structure-derived MC4R mutants, the complex structures reveal the agonist-induced origin of transmembrane helix (TM) 6-regulated receptor activation. The ligand-binding modes of NDP-α-MSH, a high-affinity linear variant of the endogenous agonist α-MSH, and setmelanotide, a cyclic anti-obesity drug with biased signaling toward Gq/11, underline the key role of TM3 in ligand-specific interactions and of calcium ion as a ligand-adaptable cofactor. The agonist-specific TM3 interplay subsequently impacts receptor-Gs-protein interfaces at intracellular loop 2, which also regulates the G-protein coupling profile of this promiscuous receptor. Finally, our structures reveal mechanistic details of MC4R activation/inhibition, and provide important insights into the regulation of the receptor signaling profile which will facilitate the development of tailored anti-obesity drugs.
Identifiants
pubmed: 34561620
doi: 10.1038/s41422-021-00569-8
pii: 10.1038/s41422-021-00569-8
pmc: PMC8563958
doi:
Substances chimiques
Receptor, Melanocortin, Type 4
0
setmelanotide
0
alpha-MSH
581-05-5
MSH, 4-Nle-7-Phe-alpha-
75921-69-6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1176-1189Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : CRC1423 - project number 421152132, Z03
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : CRC1423 - project number 394046635, A03
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : Germany's Excellence Strategies - EXC2008/1 (UniSysCat) - 390540038
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : CRC1423 - project number 421152132, A05
Informations de copyright
© 2021. The Author(s).
Références
Science. 2020 Apr 24;368(6489):428-433
pubmed: 32327598
J Pharmacol Exp Ther. 2003 Mar;304(3):1217-27
pubmed: 12604699
Front Endocrinol (Lausanne). 2019 Jul 31;10:515
pubmed: 31417496
J Mol Endocrinol. 2016 Jul;57(1):R59-80
pubmed: 27151573
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
Nat Methods. 2020 Dec;17(12):1214-1221
pubmed: 33257830
Proc Natl Acad Sci U S A. 2004 Jan 27;101(4):959-63
pubmed: 14732697
Nature. 2008 Sep 25;455(7212):497-502
pubmed: 18818650
Science. 2021 May 21;372(6544):808-814
pubmed: 33858992
Lancet Diabetes Endocrinol. 2020 Dec;8(12):960-970
pubmed: 33137293
Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
pubmed: 15299374
Nat Med. 2018 May;24(5):551-555
pubmed: 29736023
Science. 2019 May 10;364(6440):552-557
pubmed: 31073061
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
pubmed: 21460441
Int J Mol Sci. 2020 Feb 12;21(4):
pubmed: 32059383
Biochemistry. 2000 Dec 5;39(48):14900-11
pubmed: 11101306
Proc Natl Acad Sci U S A. 1980 Oct;77(10):5754-8
pubmed: 6777774
Nature. 2008 Jul 10;454(7201):183-7
pubmed: 18563085
J Comput Chem. 2004 Oct;25(13):1605-12
pubmed: 15264254
J Pediatr Endocrinol Metab. 2020 Jul 3;:
pubmed: 32619193
Nat Methods. 2015 Jul;12(7):661-663
pubmed: 26030448
Peptides. 2009 Oct;30(10):1892-900
pubmed: 19646498
Life Sci. 1996;58(20):1777-84
pubmed: 8637402
Trends Pharmacol Sci. 2011 Apr;32(4):213-8
pubmed: 21414670
Cell Metab. 2006 Feb;3(2):141-6
pubmed: 16459315
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21
pubmed: 20057044
Acta Crystallogr D Biol Crystallogr. 1999 Jan;55(Pt 1):191-205
pubmed: 10089410
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2184-95
pubmed: 15572771
N Engl J Med. 2016 Jul 21;375(3):240-6
pubmed: 27468060
N Engl J Med. 2015 Jul 2;373(1):48-59
pubmed: 26132941
J Med Chem. 1995 Sep 1;38(18):3454-61
pubmed: 7658432
Nature. 2011 Jul 19;477(7366):549-55
pubmed: 21772288
J Clin Endocrinol Metab. 2015 Apr;100(4):1639-45
pubmed: 25675384
J Mol Biol. 1994 May 20;238(5):777-93
pubmed: 8182748
Acta Crystallogr D Struct Biol. 2018 Jun 1;74(Pt 6):531-544
pubmed: 29872004
J Biol Chem. 2002 Jun 7;277(23):20328-35
pubmed: 11912210
Nature. 2015 Aug 13;524(7564):173-179
pubmed: 26147082
Biochemistry. 2005 Aug 30;44(34):11329-41
pubmed: 16114870
J Biol Chem. 1993 Oct 25;268(30):22273-6
pubmed: 8226735
Methods Enzymol. 2002;343:329-71
pubmed: 11665578
Nat Rev Drug Discov. 2008 Apr;7(4):307-23
pubmed: 18323849
Science. 2007 Nov 23;318(5854):1258-65
pubmed: 17962520
Biochim Biophys Acta Mol Basis Dis. 2017 Oct;1863(10 Pt A):2414-2435
pubmed: 28363699
Handb Exp Pharmacol. 2012;(209):47-75
pubmed: 22249810
Endocr Rev. 2010 Aug;31(4):506-43
pubmed: 20190196
Biochemistry. 2006 Jun 13;45(23):7277-88
pubmed: 16752916
Nature. 2014 Jan 9;505(7482):234-8
pubmed: 24336198
Nature. 2011 Mar 31;471(7340):651-5
pubmed: 21389988
Mol Endocrinol. 2001 Jan;15(1):164-71
pubmed: 11145747
J Clin Endocrinol Metab. 2006 May;91(5):1761-9
pubmed: 16492696
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
pubmed: 20124702
J Clin Invest. 2000 Jul;106(2):253-62
pubmed: 10903341
Biochemistry. 2005 Mar 8;44(9):3418-31
pubmed: 15736952
Eur J Pharmacol. 2005 Apr 11;512(2-3):85-95
pubmed: 15840392
Mol Cell Endocrinol. 2017 Jul 5;449:3-11
pubmed: 27899324
Mol Cell Endocrinol. 1990 Apr 17;70(2):139-45
pubmed: 2161361
Cell. 2020 Sep 17;182(6):1574-1588.e19
pubmed: 32946782
Cell Res. 2021 Oct;31(10):1061-1071
pubmed: 34453129
Nature. 2017 Jun 8;546(7657):248-253
pubmed: 28538729
Nucleic Acids Res. 2003 Jan 15;31(2):E6-6
pubmed: 12527795
Int J Mol Sci. 2020 Oct 15;21(20):
pubmed: 33076233
Neuropeptides. 1999 Jun;33(3):191-6
pubmed: 10657491
J Chem Inf Model. 2011 Oct 24;51(10):2778-86
pubmed: 21919503
Biochim Biophys Acta Mol Basis Dis. 2017 Oct;1863(10 Pt A):2462-2467
pubmed: 28499989
Nat Neurosci. 2016 Feb;19(2):206-19
pubmed: 26814590