Interactions of human melanocortin 4 receptor with nonpeptide and peptide agonists.

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.

[1]  R. Neubig,et al.  Receptor-antagonist interactions in the complexes of agouti and agouti-related protein with human melanocortin 1 and 4 receptors. , 2005, Biochemistry.

[2]  J. Metzger,et al.  Discovery of (2S)-N-[(1R)-2-[4-cyclohexyl-4-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperidinyl]-1-[(4-fluorophenyl)methyl]-2-oxoethyl]-4-methyl-2-piperazinecarboxamide (MB243), a potent and selective melanocortin subtype-4 receptor agonist. , 2005, Bioorganic & medicinal chemistry letters.

[3]  H. Levine,et al.  Complex of an active mu-opioid receptor with a cyclic peptide agonist modeled from experimental constraints. , 2004, Biochemistry.

[4]  B. Conklin,et al.  Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans. , 2004, The Journal of clinical investigation.

[5]  T. Mielke,et al.  Electron crystallography reveals the structure of metarhodopsin I , 2004, The EMBO journal.

[6]  Sviatlana Yahorava,et al.  New substituted piperazines as ligands for melanocortin receptors. Correlation to the X-ray structure of "THIQ". , 2004, Journal of medicinal chemistry.

[7]  Irina D Pogozheva,et al.  Refinement of a homology model of the mu-opioid receptor using distance constraints from intrinsic and engineered zinc-binding sites. , 2004, Biochemistry.

[8]  G Vriend,et al.  Heavier‐than‐air flying machines are impossible , 2004, FEBS letters.

[9]  C. Xiong,et al.  Biological and conformational study of beta-substituted prolines in MT-II template: steric effects leading to human MC5 receptor selectivity. , 2004, The journal of peptide research : official journal of the American Peptide Society.

[10]  Robert P Bywater,et al.  Recognition of privileged structures by G-protein coupled receptors. , 2004, Journal of medicinal chemistry.

[11]  T. I. Richardson,et al.  Synthesis and structure-activity relationships of novel arylpiperazines as potent and selective agonists of the melanocortin subtype-4 receptor. , 2004, Journal of medicinal chemistry.

[12]  Manfred Burghammer,et al.  Structure of bovine rhodopsin in a trigonal crystal form. , 2003, Journal of molecular biology.

[13]  Robert Fredriksson,et al.  High Affinity Agonistic Metal Ion Binding Sites within the Melanocortin 4 Receptor Illustrate Conformational Change of Transmembrane Region 3* , 2003, Journal of Biological Chemistry.

[14]  R. Cone,et al.  Characterization of a novel binding partner of the melanocortin-4 receptor: attractin-like protein. , 2003, The Biochemical journal.

[15]  F. Ujjainwalla,et al.  Design and syntheses of melanocortin subtype-4 receptor agonists: evolution of the pyridazinone archetype. , 2003, Bioorganic & medicinal chemistry letters.

[16]  Teresa Y. Phillips,et al.  Aryl piperazine melanocortin MC4 receptor agonists. , 2003, Bioorganic & medicinal chemistry letters.

[17]  S. Karnik,et al.  Activation of G-protein-coupled receptors: a common molecular mechanism , 2003, Trends in Endocrinology & Metabolism.

[18]  D. Segaloff,et al.  Functional characterization of melanocortin-4 receptor mutations associated with childhood obesity. , 2003, Endocrinology.

[19]  A. Sali,et al.  Comparative protein structure modeling by iterative alignment, model building and model assessment. , 2003, Nucleic acids research.

[20]  C. Haskell-Luevano,et al.  Melanocortin Tetrapeptides Modified at the N‐Terminus, His, Phe, Arg, and Trp Positions , 2003, Annals of the New York Academy of Sciences.

[21]  K. Clément,et al.  Molecular Genetics of Human Obesity‐Associated MC4R Mutations , 2003, Annals of the New York Academy of Sciences.

[22]  B. Wisse,et al.  Melanocortin Signaling and Anorexia in Chronic Disease States , 2003, Annals of the New York Academy of Sciences.

[23]  T. Schwartz,et al.  Molecular Mechanism of Agonism and Inverse Agonism in the Melanocortin Receptors , 2003, Annals of the New York Academy of Sciences.

[24]  Richard R. Neubig,et al.  Inverse agonist activity of agouti and agouti-related protein , 2003, Peptides.

[25]  S. O’Rahilly,et al.  Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms. , 2003, Human molecular genetics.

[26]  R. Maki,et al.  Molecular Determinants of Melanocortin 4 Receptor Ligand Binding and MC4/MC3 Receptor Selectivity , 2003, Journal of Pharmacology and Experimental Therapeutics.

[27]  I. Gantz,et al.  The melanocortin system. , 2003, American journal of physiology. Endocrinology and metabolism.

[28]  J. Tokarski,et al.  Discovery of tyrosine-based potent and selective melanocortin-1 receptor small-molecule agonists with anti-inflammatory properties. , 2003, Journal of medicinal chemistry.

[29]  R. Adan,et al.  Discovery and in vivo evaluation of new melanocortin-4 receptor-selective peptides , 2003, Peptides.

[30]  Jinfa Ying,et al.  Solution structures of cyclic melanocortin agonists and antagonists by NMR. , 2003, Biopolymers.

[31]  D. H. Lee,et al.  2,3-Diaryl-5-anilino[1,2,4]thiadiazoles as melanocortin MC4 receptor agonists and their effects on feeding behavior in rats. , 2003, Bioorganic & medicinal chemistry.

[32]  T. Schwartz,et al.  Metal Ion-mediated Agonism and Agonist Enhancement in Melanocortin MC1 and MC4 Receptors* , 2002, The Journal of Biological Chemistry.

[33]  D. Johnston,et al.  Design and pharmacology of N-[(3R)-1,2,3,4-tetrahydroisoquinolinium- 3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)- 2-[4-cyclohexyl-4-(1H-1,2,4-triazol- 1-ylmethyl)piperidin-1-yl]-2-oxoethylamine (1), a potent, selective, melanocortin subtype-4 receptor agonist. , 2002, Journal of medicinal chemistry.

[34]  M. Tota,et al.  The role of melanocortins in body weight regulation: opportunities for the treatment of obesity. , 2002, European journal of pharmacology.

[35]  Christopher P Austin,et al.  A role for the melanocortin 4 receptor in sexual function , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Zhimin Xiang,et al.  Structure-activity relationships of the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH(2) at the mouse melanocortin receptors. 1. Modifications at the His position. , 2002, Journal of medicinal chemistry.

[37]  K. Georgeson,et al.  Molecular Determinants of Human Melanocortin-4 Receptor Responsible for Antagonist SHU9119 Selective Activity* , 2002, The Journal of Biological Chemistry.

[38]  Ruth Nussinov,et al.  Principles of docking: An overview of search algorithms and a guide to scoring functions , 2002, Proteins.

[39]  K. Chapman,et al.  Combinatorial synthesis of 3-(amidoalkyl) and 3-(aminoalkyl)-2-arylindole derivatives: discovery of potent ligands for a variety of G-protein coupled receptors. , 2002, Bioorganic & medicinal chemistry letters.

[40]  K. Palczewski,et al.  Crystal Structure of Rhodopsin: A G‐Protein‐Coupled Receptor , 2002, Chembiochem : a European journal of chemical biology.

[41]  E. Meng,et al.  Receptor activation: what does the rhodopsin structure tell us? , 2001, Trends in pharmacological sciences.

[42]  C. Haskell-Luevano,et al.  Agouti-related protein functions as an inverse agonist at a constitutively active brain melanocortin-4 receptor , 2001, Regulatory Peptides.

[43]  W. Wilkison,et al.  Melanocortin receptor-mediated mobilization of intracellular free calcium in HEK293 cells. , 2001, Physiological genomics.

[44]  T. Lundstedt,et al.  PLS modeling of chimeric MS04/MSH-peptide and MC1/MC3-receptor interactions reveals a novel method for the analysis of ligand-receptor interactions. , 2001, Biochimica et biophysica acta.

[45]  R. Adan,et al.  AgRP(83-132) acts as an inverse agonist on the human-melanocortin-4 receptor. , 2001, Molecular endocrinology.

[46]  Krzysztof Palczewski,et al.  Crystal Structure of Rhodopsin: A G‐Protein‐Coupled Receptor , 2002, Science.

[47]  J Lindblom,et al.  New aspects on the melanocortins and their receptors. , 2000, Pharmacological research.

[48]  M. Tota,et al.  Molecular determinants of ligand binding to the human melanocortin-4 receptor. , 2000, Biochemistry.

[49]  A V Vergoni,et al.  Role of melanocortins in the central control of feeding. , 2000, European journal of pharmacology.

[50]  M. Bednarek,et al.  Analogs of Lactam Derivatives of α-Melanotropin with Basic and Acidic Residues , 2000 .

[51]  R. Cone,et al.  Agouti and Agouti-related Protein: Analogies and Contrasts* , 2000, The Journal of Biological Chemistry.

[52]  R. Cone,et al.  Structure activity studies of the melanocortin antagonist SHU9119 modified at the 6, 7, 8, and 9 positions☆ , 2000, Peptides.

[53]  M. Bednarek,et al.  Analogs of lactam derivatives of alpha-melanotropin with basic and acidic residues. , 2000, Biochemical and biophysical research communications.

[54]  B. Pettitt,et al.  Modeling of alpha-MSH conformations with implicit solvent. , 1999, The journal of peptide research : official journal of the American Peptide Society.

[55]  J. Wikberg,et al.  Discovery of a novel superpotent and selective melanocortin-4 receptor antagonist (HS024): evaluation in vitro and in vivo. , 1998, Endocrinology.

[56]  V. Hruby,et al.  Studies of conformational isomerism in alpha-melanocyte stimulating hormone by design of cyclic analogues. , 1998, Biopolymers.

[57]  A. Lomize,et al.  Opioid receptor three-dimensional structures from distance geometry calculations with hydrogen bonding constraints. , 1998, Biophysical journal.

[58]  J. Burbach,et al.  Asp10 in Lys-gamma2-MSH determines selective activation of the melanocortin MC3 receptor. , 1998, European journal of pharmacology.

[59]  P. Prusis,et al.  Discovery of novel melanocortin4 receptor selective MSH analogues , 1998, British journal of pharmacology.

[60]  P Herzyk,et al.  Modeling of the three-dimensional structure of the human melanocortin 1 receptor, using an automated method and docking of a rigid cyclic melanocyte-stimulating hormone core peptide. , 1997, Journal of molecular graphics & modelling.

[61]  I. Gantz,et al.  Molecular Basis for the Interaction of [Nle4,d-Phe7]Melanocyte Stimulating Hormone with the Human Melanocortin-1 Receptor (Melanocyte α-MSH Receptor)* , 1997, The Journal of Biological Chemistry.

[62]  H. Schiöth,et al.  Deletions of the N‐terminal regions of the human melanocortin receptors , 1997, FEBS letters.

[63]  V. Hruby,et al.  Biological and conformational examination of stereochemical modifications using the template melanotropin peptide, Ac-Nle-c[Asp-His-Phe-Arg-Trp-Ala-Lys]-NH2, on human melanocortin receptors. , 1997, Journal of medicinal chemistry.

[64]  A. Lomize,et al.  The transmembrane 7-alpha-bundle of rhodopsin: distance geometry calculations with hydrogen bonding constraints. , 1997, Biophysical journal.

[65]  W. Wilkison,et al.  Interactions of alpha-melanotropin and agouti on B16 melanoma cells: evidence for inverse agonism of agouti. , 1997, Journal of receptor and signal transduction research.

[66]  H. Khorana,et al.  Requirement of Rigid-Body Motion of Transmembrane Helices for Light Activation of Rhodopsin , 1996, Science.

[67]  R. Cone,et al.  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. , 1995, Journal of medicinal chemistry.

[68]  P. Prusis,et al.  A three dimensional model for the interaction of MSH with the melanocortin-1 receptor. , 1995, Biochemical and biophysical research communications.

[69]  J. Ballesteros,et al.  [19] Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors , 1995 .

[70]  S. Watson,et al.  The G-Protein Linked Receptor Facts Book , 1994 .

[71]  K Wüthrich,et al.  Improved efficiency of protein structure calculations from NMR data using the program DIANA with redundant dihedral angle constraints , 1991, Journal of biomolecular NMR.

[72]  H. Motulsky,et al.  Calculating receptor number from binding experiments using same compound as radioligand and competitor. , 1989, Trends in pharmacological sciences.

[73]  V. Hruby,et al.  Design of a new class of superpotent cyclic α-melanotropins based on quenched dynamic simulations , 1989 .

[74]  V. Hruby,et al.  Cyclic lactam analogues of Ac-[Nle4]alpha-MSH4-11-NH2. , 1988, Biochemistry.

[75]  V J Hruby,et al.  alpha-Melanotropin: the minimal active sequence in the frog skin bioassay. , 1987, Journal of medicinal chemistry.

[76]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[77]  V. Hruby,et al.  [half-Cys4,half-Cys10]-alpha-Melanocyte-stimulating hormone: a cyclic alpha-melanotropin exhibiting superagonist biological activity. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[78]  V. Hruby,et al.  Calcium-dependent prolonged effects on melanophores of [4-norleucine, 7-D-phenylalanine]-alpha-melanotropin. , 1981, Science.

[79]  V. Hruby,et al.  4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity. , 1980, Proceedings of the National Academy of Sciences of the United States of America.