Synthesis and biological evaluation of α-MSH analogues substituted with alanine

Sahm, U.G.; Olivier, George; Branch, Sarah K.; Moss, S. H.; Pouton, Colin W.

doi:10.1016/0196-9781(94)90157-0

Cited by 79 publications

(94 citation statements)

References 25 publications

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“…An inactivation study based on alanine substitutions determined the relative importance of each amino acid in the ␣-MSH sequence in binding activity of ␣-MSH to human MC1R and rat MC3R (Sahm et al, 1994). This Ala-scan showed the importance of the amino acids in position 4 -10 for binding to both these receptors (Sahm et al, 1994).…”

Section: Structure-activity Relationship Of Melanocortin Peptidesmentioning

confidence: 99%

Targeting Melanocortin Receptors as a Novel Strategy to Control Inflammation

Catania

Gatti

Colombo

et al. 2004

Pharmacological Reviews

418

500

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Section: Structure-activity Relationship Of Melanocortin Peptidesmentioning

confidence: 99%

Targeting Melanocortin Receptors as a Novel Strategy to Control Inflammation

Catania

Gatti

Colombo

et al. 2004

Pharmacological Reviews

418

500

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“…This indicates that introduction of these residues in [Nle 4 ]␣-MSH prohibited interaction with both receptors. In a previous study (32) ]␣-MSH are probably not important for a direct interaction with the receptor, since Ala substitution on positions 10 and 11 of ␣-MSH did not affect affinity on the MC3R nor the MC1R (23).…”

Section: And [D-tyr 4 ]Mt-ii On Mc4r Mc4(267-282 Mc3) Mc4(y268i)mentioning

confidence: 99%

“…Nevertheless, it has been demonstrated that HFRW (MSH (6 -9)) forms the core sequence of melanocortins, which is necessary to bind to all MC receptors (21)(22)(23). Ligand selectivity may therefore be determined by residues outside the core region either through a selective interaction with different receptor subtypes, by altering folding of the core sequence, or by a combination of both.…”

mentioning

confidence: 99%

Conformation of the Core Sequence in Melanocortin Peptides Directs Selectivity for the Melanocortin MC3 and MC4 Receptors

Oosterom

Nijenhuis

Schaaper³

et al. 1999

Journal of Biological Chemistry

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Melanocortin peptides regulate a variety of physiological processes. Five melanocortin receptors (MC-RMT-II, that also displayed lower affinity for the MC3R. This study provides a general concept for peptide receptor selectivity, in which the major determinant for a selective receptor interaction is the conformational presentation of the core sequence in related peptides to the receptor-binding pocket.

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“…These receptors are activated by a group of peptides derived from post-translational processing of the pro-opiomelanocortin gene transcript. These peptides include ␣-melanocyte-stimulating hormone (␣-MSH) and adrenocorticotropin hormone (ACTH), both of which contain the common amino acid sequence His6-Phe7-Arg8-Trp9 (Sahm et al, 1994;Haskell-Luevano et al, 1997). Melanocortin receptor activation is modulated by two endogenous antagonists/inverse agonists, agouti and agouti-related protein (AGRP) (Lu et al, 1994;Ollmann et al, 1997).…”

mentioning

confidence: 99%

Molecular Determinants of Melanocortin 4 Receptor Ligand Binding and MC4/MC3 Receptor Selectivity

Nickolls

Cismowski²,

Wang³

et al. 2003

The Journal of Pharmacology and Experimental Therapeutics

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The molecular basis of ligand recognition by the melanocortin 4 receptor (MC4R) has not been fully defined. In this study, we investigated the molecular determinants of MC4R ligand binding, employing a large array of ligands, using three approaches. First, molecular modeling of the receptor was used to identify Phe284, in transmembrane (TM) 7, as a potential site of ligand interaction. Mutation of Phe284 to alanine reduced binding affinity and potency of peptides containing L-Phe by up to 71-fold but did not appreciably affect binding of linear peptides containing D-Phe, consistent with a hydrophobic interaction between the Phe7 of ␣-melanocyte-stimulating hormone and Phe284. Second, we examined the effect of a naturally occurring mutation in TM3 (I137T) that is linked to obesity. This mutation decreased affinity and potency of cyclic, rigid peptides but not more flexible peptides, consistent with an indirect effect of the mutation on the tertiary structure of the receptor. Third, we examined the residues that support ligand selectivity for the MC4R over the MC3R. Mutation of Ile125 (TM3) of the MC4R to the equivalent residue of the MC3R (phenylalanine) selectively decreased affinity and potency of MC4R-selective ligands. This effect was mirrored by the reciprocal MC3R mutation F157I. The magnitude of this effect indicates that this locus is not of major importance. However, it is considered that an isoleucine/phenylalanine mutation may affect the orientation of Asp122, which has been identified as a major determinant of ligand binding affinity. Thus, this study provides further characterization of the MC4R binding pocket.

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Synthesis and biological evaluation of α-MSH analogues substituted with alanine

Cited by 79 publications

References 25 publications

Targeting Melanocortin Receptors as a Novel Strategy to Control Inflammation

Targeting Melanocortin Receptors as a Novel Strategy to Control Inflammation

Conformation of the Core Sequence in Melanocortin Peptides Directs Selectivity for the Melanocortin MC3 and MC4 Receptors

Molecular Determinants of Melanocortin 4 Receptor Ligand Binding and MC4/MC3 Receptor Selectivity

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