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J Chem Inf Model. 2020 Feb 6. doi: 10.1021/acs.jcim.9b01196. [Epub ahead of print]

Combined Computational and Structural Approach into Understanding the Role of Peptide Binding and Activation of Melanocortin Receptor 4.

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Department of Biostatistics , Autonomous University of Barcelona , 08193 Bellaterra , Spain.
Institute of Chemical Biology , National Hellenic Research Foundation , 11635 Athens , Greece.
Department of Chemistry , University of Patras , 26500 Patras , Greece.
Department of Pharmacy , University of Patras , 26500 Patras , Greece.


Melanocortin receptor 4 (MC4R) is expressed predominantly in the central nervous system and regulates food intake and sexual function and is also thought to be responsible for effects on mood and cognition. It belongs to the melanocortin receptor subfamily of G protein-coupled receptors (GPCRs). Here, we have synthesized and structurally characterized three peptides that bind to MC4R, producing different signaling events. AgRP is a naturally occurring antagonist, HLWNRS is the minimal sequence of the N-terminal with partial agonist activity, and aMSH is a full agonistic peptide. By implementing molecular dynamics simulations on the different peptide-receptor complexes, we propose their molecular basis of binding to investigate their differential molecular properties regarding the activation states of the receptor. Our analysis shows that the agonist and partial agonist may induce rotation in transmembrane helix 3, which is known to be involved in the key events occurring during GPCR activation, and this movement is impacted by certain aromatic residues and their positioning in the orthosteric binding site of the receptor.


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