ArticleBiochemistry2005
Interactions of human melanocortin 4 receptor with nonpeptide and peptide agonists.
Article in Biochemistry, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 92 citations in OpenAlex.
- Article
- Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-α-MSH and setmelanotide.Cell research · 2021Article
- Hypothesis and Theory: Evaluating the Co-Evolution of the Melanocortin-2 Receptor and the Accessory Protein MRAP1.Frontiers in endocrinology · 2021Article
- 7,3',4'-Trihydroxyisoflavone, a Metabolite of the Soy Isoflavone Daidzein, Suppresses α-Melanocyte-Stimulating Hormone-Induced Melanogenesis by Targeting Melanocortin 1 Receptor.Frontiers in molecular biosciences · 2020Article
- Identifying Common Features in the Activation of Melanocortin-2 Receptors: Studies on theInternational journal of molecular sciences · 2019Article
- Insights into the Allosteric Mechanism of Setmelanotide (RM-493) as a Potent and First-in-Class Melanocortin-4 Receptor (MC4R) Agonist To Treat Rare Genetic Disorders of Obesity through an in Silico Approach.ACS chemical neuroscience · 2019Article
- From Bioinactive ACTH to ACTH Antagonist: The Clinical Perspective.Frontiers in endocrinology · 2017Review
- ACTH Receptor (MC2R) Specificity: What Do We Know About Underlying Molecular Mechanisms?Frontiers in endocrinology · 2017Review
- ACTH Antagonists.Frontiers in endocrinology · 2016Review
- Hypothesis and Theory: Revisiting Views on the Co-evolution of the Melanocortin Receptors and the Accessory Proteins, MRAP1 and MRAP2.Frontiers in endocrinology · 2016Article
- Azepinone-Containing Tetrapeptide Analogues of Melanotropin Lead to Selective hMC4R Agonists and hMC5R Antagonist.ACS medicinal chemistry letters · 2015Article
- Biased signaling in naturally occurring mutations in human melanocortin-3 receptor gene.International journal of biological sciences · 2015Article
- Molecular and functional analysis of human β-defensin 3 action at melanocortin receptors.Chemistry & biology · 2013Article
- Observations on the evolution of the melanocortin receptor gene family: distinctive features of the melanocortin-2 receptor.Frontiers in neuroscience · 2013Article
- Identification of an MRAP-independent melanocortin-2 receptor: functional expression of the cartilaginous fish, Callorhinchus milii, melanocortin-2 receptor in CHO cells.Endocrinology · 2012Article
- Influence of genomic variation in FTO at 16q12.2, MC4R at 18q22 and NRXN3 at 14q31 genes on breast cancer risk.Molecular biology reports · 2012Article
- Conformational study on cyclic melanocortin ligands and new insight into their binding mode at the MC4 receptor.European journal of medicinal chemistry · 2011Article
- Salt bridges overlapping the gonadotropin-releasing hormone receptor agonist binding site reveal a coincidence detector for G protein-coupled receptor activation.The Journal of pharmacology and experimental therapeutics · 2011Article
- Structure, function and regulation of the melanocortin receptors.European journal of pharmacology · 2011Review
- Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Specific interactions of human melanocortin-4 receptor (hMC4R) with its nonpeptide and peptide agonists were studied using alanine-scanning mutagenesis. The binding affinities and potencies of two synthetic, small-molecule agonists (THIQ, MB243) were strongly affected by substitutions in transmembrane alpha-helices (TM) 2, 3, 6, and 7 (residues Glu(100), Asp(122), Asp(126), Phe(261), His(264), Leu(265), and Leu(288)). In addition, a I129A mutation primarily affected the binding and potency of THIQ, while F262A, W258A, Y268A mutations impaired interactions with MB243. By contrast, binding affinity and potency of the linear peptide agonist NDP-MSH were substantially reduced only in D126A and H264A mutants. Three-dimensional models of receptor-ligand complexes with their agonists were generated by distance-geometry using the experimental, homology-based, and other structural constraints, including interhelical H-bonds and two disulfide bridges (Cys(40)-Cys(279), Cys(271)-Cys(277)) of hMC4R. In the models, all pharmacophore elements of small-molecule agonists are spatially overlapped with the corresponding key residues (His(6), d-Phe(7), Arg(8), and Trp(9)) of the linear peptide: their charged amine groups interact with acidic residues from TM2 and TM3, similar to His(6) and Arg(6) of NDP-MSH; their substituted piperidines mimic Trp(9) of the peptide and interact with TM5 and TM6, while the d-Phe aromatic rings of all three agonists contact with Leu(133), Trp(258), and Phe(261) residues.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.