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TitleStructural mechanism of CBR binding to peripheral and biased inverse agonists.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 10694, Year 2024
Publish dateDec 18, 2024
AuthorsPunita Kumari / Szabolcs Dvorácskó / Michael D Enos / Karthik Ramesh / Darrix Lim / Sergio A Hassan / George Kunos / Resat Cinar / Malliga R Iyer / Daniel M Rosenbaum /
PubMed AbstractThe cannabinoid receptor 1 (CBR) regulates synaptic transmission in the central nervous system, but also has important roles in the peripheral organs controlling cellular metabolism. While earlier ...The cannabinoid receptor 1 (CBR) regulates synaptic transmission in the central nervous system, but also has important roles in the peripheral organs controlling cellular metabolism. While earlier generations of brain penetrant CBR antagonists advanced to the clinic for their effective treatment of obesity, such molecules were ultimately shown to exhibit negative effects on central reward pathways that thwarted their further therapeutic development. The peripherally restricted CBR inverse agonists MRI-1867 and MRI-1891 represent a new generation of compounds that retain the metabolic benefits of CBR inhibitors while sparing the negative psychiatric effects. To understand the mechanism of binding and inhibition of CBR by peripherally restricted antagonists, we developed a nanobody/fusion protein strategy for high-resolution cryo-EM structure determination of the GPCR inactive state, and used this method to determine structures of CBR bound to either MRI-1867 or MRI-1891. These structures reveal how these compounds retain high affinity and specificity for CBR's hydrophobic orthosteric site despite incorporating polar functionalities that lead to peripheral restriction. Further, the structure of the MRI-1891 complex along with accompanying molecular dynamics simulations shows how differential engagement with transmembrane helices and the proximal N-terminus can propagate through the receptor to contribute to biased inhibition of β-arrestin signaling.
External linksNat Commun / PubMed:39695122 / PubMed Central
MethodsEM (single particle)
Resolution3.13 - 3.5 Å
Structure data

44392

9b9y

EMDB-44392, PDB-9b9y:
Structural mechanism of CB1R binding to peripheral and biased inverse agonists
Method: EM (single particle) / Resolution: 3.5 Å

44393

9b9z

EMDB-44393, PDB-9b9z:
Structural mechanism of CB1R binding to peripheral and biased inverse agonists
Method: EM (single particle) / Resolution: 3.3 Å

44394

9ba0

EMDB-44394, PDB-9ba0:
Structural mechanism of CB1R binding to peripheral and biased inverse agonists
Method: EM (single particle) / Resolution: 3.13 Å

Chemicals

ChemComp-7DY:
N-[(2S,3S)-4-(4-chlorophenyl)-3-(3-cyanophenyl)butan-2-yl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide / agonist*YM

PDB-1ako:
EXONUCLEASE III FROM ESCHERICHIA COLI

PDB-1akn:
STRUCTURE OF BILE-SALT ACTIVATED LIPASE

Source
  • homo sapiens (human)
  • lama glama (llama)
  • pyrococcus abyssi ge5 (archaea)
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / obesity / membrane protein / nanobody / SIGNALING PROTEIN-IMMUNE SYSTEM complex

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