Peptide and protein biological activities depend on their three dimensionals structures in the free state and when interacting with their receptors/acceptors. The backbone conformations such as α‐helix, β‐sheet, β‐turn, and so forth provide critical templates for the three‐dimensional structure, but the overall shape and intrinsic stereoelectronic properties of the peptide or protein important for molecular recognition, signal transduction, enzymatic specificity, immunomodulation, and other biological effects depend on arrangement of the side chain groups in three‐dimensional chi space (their χ1, χ2, etc. torsional angles) In this paper we explore approaches to the de novo design of polypeptides and peptidomimetics with biased or specific conformational/topographical properties in chi space. We consider computational and experimental methods that can be used to examine the effects of specific structural modifications in constraining side chain groups of amino acid residues and their similarities in chi space to the natural amino acids to evaluate what sort of mimetics are likely to minic normal amino acids. We then examine some of the asymmetric synthetic methods that are being developed to obtain the amino acid mimetics. Finally, we consider selected examples in the literature where these specialized amino acids have been incorporated in biologically active peptides and the specific insights they have provided regarding the topographical requirements for bioactive peptide potency, selectivity, and other biochemical and pharmacological properties. Constraints in chi space show great promise as useful tools in peptide, protein, and peptidomimetic de novo design of structures and pharmacophores with specific stereostructural, biochemical and biological properties. © 1997 John Wiley & Sons, Inc. Biopoly 43: 219–266, 1997
In vitro mutagenesis of the mouse melanocortin-4 receptor (mMC4R) has been performed, based upon homology molecular modeling and previous melanocortin receptor mutagenesis studies that identified putative ligand-receptor interactions. Twenty-three mMC4 receptor mutants were generated and pharmacologically characterized using several melanocortin-based ligands [alpha-MSH, NDP-MSH, MTII, DNal (1')(7)-MTII, Nal(2')(7)-MTII, SHU9119, and SHU9005]. Selected mutant receptors possessing significant differences in the melanocortin-based peptide agonist and/or antagonist pharmacology were further evaluated using the endogenous antagonist agouti-related protein fragment hAGRP(83-132) and hAGRP(109-118) molecules. These studies of the mouse MC4R provide further experimental data suggesting that the conserved melanocortin receptor residues Glu92 (TM2), Asp114 (TM3), and Asp118 (TM3) (mouse MC4R numbering) are important for melanocortin-based peptide molecular recognition. Additionally, the Glu92 and Asp118 mMC4R residues are important for molecular recognition and binding of AGRP(83-132). We have identified the Phe176 (TM4), Tyr179 (TM4), Phe254 (TM6), and Phe259 (TM6) receptor residues as putatively interacting with the melanocortin-based ligand Phe(7) by differences between alpha-MSH and NDP-MSH agonist potencies. The Glu92, Asp118, and Phe253 mMC4R receptor residues appear to be critical for hAGRP(83-132) molecular recognition and binding while Phe176 appears to be important for functional antagonism of AGRP(83-132) and AGRP(109-118) but not molecular recognition. The Phe253 mMC4R residue appears to be important for AGRP(83-132) molecular recognition and general mMC4 receptor stimulation. The Phe254 and Phe259 mMC4R amino acids may participate in the differentiation of agonist versus antagonist activity of the melanocortin-based peptide antagonists SHU9119 and SHU9005, but not AGRP(83-132) or AGRP(109-118). The Met192 side chain when mutated to a Phe results in a constitutively active mMC4R that does not effect agonist ligand binding or potency. Melanocortin-based peptides modified at the 7 position of MTII with DPhe, DNal(1'), Nal(2'), and DNal(2') have been pharmacologically characterized at these mutant mouse MC4Rs. These data suggest a revised hypothesis for the mechanism of SHU9119 antagonism at the MC4R which may be attributed to the presence of a "bulky" naphthyl moiety at the 7 position (original hypothesis), and additionally that both the stereochemistry and naphthyl ring position (2' versus 1') are important for positioning of the ligand Arg(8) residue with the corresponding mMC4R amino acids.
The melanocortin-1 receptor (MC1R) is a seven-transmembrane (TM) G-protein-coupled receptor whose natural ligands are the melanocortin peptides, adrenocorticotropic hormone, and ␣-, -, and ␥-melanocyte stimulating hormone (MSH). To test a previously constructed three-dimensional model of the molecular interaction between the long-acting, superpotent , and simultaneous mutation of multiple TM4, -5, and -6 tyrosine and phenylalanine residues suggests that aromatic-aromatic ligand-receptor interactions also participate in binding these melanocortins to the MC1R. These experiments appear to have identified some of the critical receptor residues involved in the ligand-receptor interactions between these melanocortins and the hMC1R.The term melanocortin refers to several of the post-translational products of the pro-opiomelanocortin gene, adrenocorticotropic hormone (ACTH), 1 and ␣-, -, and ␥-MSH. Besides the well known effects of these peptides on adrenal cortical steroidogenesis (ACTH) and pigmentation (␣-MSH and ACTH), melanocortins have also been implicated in a myriad of physiological processes including learning and memory, blood pressure control, immune modulation, and weight homeostasis among others (1-3).All melanocortin peptides contain a core or "message" HisPhe-Arg-Trp sequence and, with the exception of ␥-MSH, also share a common heptapeptide sequence Met-Glu-His-Phe-ArgTrp-Gly (Fig. 1) MT-II)) (4, 5). Both NDP-MSH and MT-II have extremely prolonged activity (days) as compared with ␣-MSH (hours) in the classical frog and lizard skin darkening bioassays (4, 5).There is some evidence to suggest that the basis for this residual activity lies, at least in part, on the slow dissociation rates of these ␣-MSH analogs (6). This unique property of prolonged activity makes an understanding of the molecular interactions of these two compounds with its target receptors of particular interest.To date five melanocortin receptor subtypes with different patterns of tissue expression in the central nervous system and peripheral body have been cloned. Designated melanocortin receptor (MCR) 1-5 for the order in which they were isolated, all five receptor subtypes belong to the family of seven transmembrane G-protein-coupled receptors and upon stimulation all subtypes activate adenylate cyclase and elevate intracellular 3Ј,5Ј-adenosine monophosphate. A unified nomenclature has been set forth in which the melanocyte melanocortin receptor, previously referred to as the ␣-MSH receptor, has been designated the melanocortin-1 receptor (MC1R). This newer terminology was adopted since studies with the cloned melanocortin receptor subtypes have demonstrated that with the exception of the melanocortin-2 receptor (the adrenocortical ACTH receptor) which is only activated by ACTH, all other subtypes are promiscuous in their activation by the melanocortins.Each of the five MCR subtypes has its own signature profile of melanocortin activation. The human MC1R (hMC1R) is activated equally well by both ACTH and ␣-MSH while -MSH is appro...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.