Molecular mechanism
Melanocortin receptors
A family of five G protein-coupled receptors, MC1R through MC5R. ACTH recognition and signaling at MC2R depend on the accessory protein MRAP. Native hormones, peptide analogs and nonpeptide ligands differ in receptor-subtype recognition and functional direction; binding affinity, agonism and antagonism must be interpreted separately in the experimental system studied.
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Neutral molecular overview
A family of five G protein-coupled receptors, MC1R through MC5R. ACTH recognition and signaling at MC2R depend on the accessory protein MRAP. Native hormones, peptide analogs and nonpeptide ligands differ in receptor-subtype recognition and functional direction; binding affinity, agonism and antagonism must be interpreted separately in the experimental system studied.
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Target identifiers
- Gene symbols
- MC1R, MC2R, MC3R, MC4R, MC5R
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Related compounds
Compound
Melanotan I (Afamelanotide)
Afamelanotide, widely supplied as Melanotan I, is a linear thirteen-residue analog of alpha-melanocyte-stimulating hormone carrying norleucine and D-phenylalanine substitutions.
Compound
alpha-MSH
alpha-MSH is the endogenous thirteen-residue melanocortin peptide hormone from which several of the synthetic compounds in this library are derived.
Compound
PT-141 (Bremelanotide)
PT-141, canonically bremelanotide, is a synthetic cyclic heptapeptide melanocortin receptor agonist, structurally the C-terminal free acid of the Melanotan II lactam scaffold.
Compound
Cosyntropin (ACTH 1-24)
Cosyntropin is the synthetic 1-24 fragment of adrenocorticotropic hormone, the melanocortin ligand of the MC2R branch.
Compound
Melanotan II
Melanotan II is a synthetic cyclic heptapeptide analog of alpha-melanocyte-stimulating hormone, closed by a lactam bridge between an aspartate and a lysine side chain.
Compound
Setmelanotide
Setmelanotide is a synthetic disulfide-cyclized octapeptide characterised as an MC4R-preferring melanocortin receptor agonist.
Compound
SHU9119
SHU9119 is a cyclic lactam melanocortin analog whose receptor behaviour is subtype-dependent: antagonist at some melanocortin receptors and agonist at others.
Compound
THIQ
THIQ is a nonpeptide small-molecule agonist at the melanocortin-4 receptor, included here as the nonpeptide comparator to the melanocortin peptides.
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Related mechanisms
No related mechanism is declared in this seed record.
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Verified bibliography
- Structure-function studies on the cyclic peptide MT-II, lactam derivative of alpha-melanotropin.current
Bednarek MA, Silva MV, Arison B, MacNeil T, Kalyani RN, Huang RR, Weinberg DH
Peptides · 1999 · Journal Article
- Structural insights into ligand recognition and activation of the melanocortin-4 receptor.current
Zhang H, Chen LN, Yang D, Mao C, Shen Q, Feng W, Shen DD, Dai A, Xie S, Zhou Y, Qin J, Sun JP, Scharf DH, Hou T, Zhou T, Wang MW, Zhang Y
Cell research · 2021-08-25 · Journal Article
- Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-α-MSH and setmelanotide.current
Heyder NA, Kleinau G, Speck D, Schmidt A, Zschunke S, Szczepek M, Bauer B, Koch A, Gallandi M, Kwiatkowski D, Bürger J, Mielke T, Beck-Sickinger AG, Hildebrand PW, Spahn CMT, Hilger D, Schacherl M, Biebermann H, Hilal T, Kühnen P, Kobilka BK, Scheerer P
Cell research · 2021-09-24 · Journal Article
- 4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity.current
Sawyer TK, Sanfilippo PJ, Hruby VJ, Engel MH, Heward CB, Burnett JB, Hadley ME
Proceedings of the National Academy of Sciences of the United States of America · 1980-10 · Journal Article
- Molecular basis for the interaction of [Nle4,D-Phe7]melanocyte stimulating hormone with the human melanocortin-1 receptor.current
Yang Yk, Dickinson C, Haskell-Luevano C, Gantz I
The Journal of biological chemistry · 1997-09-12 · Journal Article
- Structural mechanism of calcium-mediated hormone recognition and Gβ interaction by the human melanocortin-1 receptor.current
Ma S, Chen Y, Dai A, Yin W, Guo J, Yang D, Zhou F, Jiang Y, Wang MW, Xu HE
Cell research · 2021-08-27 · Journal Article
- CLIPSing Melanotan-II to Discover Multiple Functionally Selective hMCR Agonists.current
Tomassi S, Dimmito MP, Cai M, D'Aniello A, Del Bene A, Messere A, Liu Z, Zhu T, Hruby VJ, Stefanucci A, Cosconati S, Mollica A, Di Maro S
Journal of medicinal chemistry · 2022-02-21 · Journal Article
- Goldilocks-Inspired Design of Mid-Size Macrocycles for Selective Targeting of Human Melanocortin Receptors.current
Merlino F, Jia L, Boccino I, Carotenuto A, Tammaro F, Santoro F, Thompson PE, Grieco P
Journal of medicinal chemistry · 2026-08-13 · Journal Article
- Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors.current
Hruby VJ, Lu D, Sharma SD, Castrucci AL, Kesterson RA, al-Obeidi FA, Hadley ME, Cone RD
Journal of medicinal chemistry · 1995-09-01 · Journal Article
- Determination of the melanocortin-4 receptor structure identifies Ca(2+) as a cofactor for ligand binding.current
Yu J, Gimenez LE, Hernandez CC, Wu Y, Wein AH, Han GW, McClary K, Mittal SR, Burdsall K, Stauch B, Wu L, Stevens SN, Peisley A, Williams SY, Chen V, Millhauser GL, Zhao S, Cone RD, Stevens RC
Science (New York, N.Y.) · 2020-04-24 · Journal Article
- Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling.current
Israeli H, Degtjarik O, Fierro F, Chunilal V, Gill AK, Roth NJ, Botta J, Prabahar V, Peleg Y, Chan LF, Ben-Zvi D, McCormick PJ, Niv MY, Shalev-Benami M
Science (New York, N.Y.) · 2021-04-15 · Journal Article
- Interactions of human melanocortin 4 receptor with nonpeptide and peptide agonists.current
Pogozheva ID, Chai BX, Lomize AL, Fong TM, Weinberg DH, Nargund RP, Mulholland MW, Gantz I, Mosberg HI
Biochemistry · 2005-08-30 · Journal Article
- Key amino acid residues in the melanocortin-4 receptor for nonpeptide THIQ specific binding and signaling.current
Yang Y, Cai M, Chen M, Qu H, McPherson D, Hruby V, Harmon CM
Regulatory peptides · 2009-03-20 · Journal Article
- Adrenocorticotropic Hormone (ACTH) Responses Require Actions of the Melanocortin-2 Receptor Accessory Protein on the Extracellular Surface of the Plasma Membrane.current
Malik S, Dolan TM, Maben ZJ, Hinkle PM
The Journal of biological chemistry · 2015-09-30 · Journal Article
- Use of chimeric melanocortin-2 and -4 receptors to identify regions responsible for ligand specificity and dependence on melanocortin 2 receptor accessory protein.current
Hinkle PM, Serasinghe MN, Jakabowski A, Sebag JA, Wilson KR, Haskell-Luevano C
European journal of pharmacology · 2011-01-03 · Journal Article
- Structural basis of signaling regulation of the human melanocortin-2 receptor by MRAP1.current
Luo P, Feng W, Ma S, Dai A, Wu K, Chen X, Yuan Q, Cai X, Yang D, Wang MW, Eric Xu H, Jiang Y
Cell research · 2023-01-02 · Journal Article
- Dissection of the anti-inflammatory effect of the core and C-terminal (KPV) alpha-melanocyte-stimulating hormone peptides.current
Getting SJ, Schiöth HB, Perretti M
The Journal of pharmacology and experimental therapeutics · 2003-05-15 · Journal Article
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Related glossary terms
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Related Purely Peptides research articles
No existing Research Article is mapped to this mechanism seed record.