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Structures of active melanocortin-4 receptor–Gs-protein complexes with NDP-α-MSH and setmelanotide

Overview of attention for article published in Cell Research, September 2021
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About this Attention Score

  • In the top 5% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (97th percentile)
  • High Attention Score compared to outputs of the same age and source (87th percentile)

Mentioned by

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11 news outlets
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23 X users
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1 Facebook page

Citations

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37 Dimensions

Readers on

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69 Mendeley
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Title
Structures of active melanocortin-4 receptor–Gs-protein complexes with NDP-α-MSH and setmelanotide
Published in
Cell Research, September 2021
DOI 10.1038/s41422-021-00569-8
Pubmed ID
Authors

Nicolas A. Heyder, Gunnar Kleinau, David Speck, Andrea Schmidt, Sarah Paisdzior, Michal Szczepek, Brian Bauer, Anja Koch, Monique Gallandi, Dennis Kwiatkowski, Jörg Bürger, Thorsten Mielke, Annette G. Beck-Sickinger, Peter W. Hildebrand, Christian M. T. Spahn, Daniel Hilger, Magdalena Schacherl, Heike Biebermann, Tarek Hilal, Peter Kühnen, Brian K. Kobilka, Patrick Scheerer

Abstract

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.

X Demographics

X Demographics

The data shown below were collected from the profiles of 23 X users who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 69 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 69 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 13 19%
Student > Ph. D. Student 10 14%
Student > Master 4 6%
Student > Bachelor 4 6%
Student > Doctoral Student 3 4%
Other 8 12%
Unknown 27 39%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 12 17%
Agricultural and Biological Sciences 6 9%
Neuroscience 6 9%
Pharmacology, Toxicology and Pharmaceutical Science 5 7%
Chemistry 5 7%
Other 6 9%
Unknown 29 42%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 88. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 07 July 2022.
All research outputs
#482,097
of 25,363,868 outputs
Outputs from Cell Research
#52
of 2,054 outputs
Outputs of similar age
#11,798
of 434,697 outputs
Outputs of similar age from Cell Research
#5
of 31 outputs
Altmetric has tracked 25,363,868 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 98th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 2,054 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 19.8. This one has done particularly well, scoring higher than 97% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 434,697 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 97% of its contemporaries.
We're also able to compare this research output to 31 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 87% of its contemporaries.