Research article summary (published 18 Oct 2009):

Novel binding motif of ACTH analogues at the melanocortin receptors.

Full Abstract

The melanocortin receptor (MCR) subtype family is a member of the GPCR superfamily, and each of them has a different pharmacological profile with regard to the relative potency of the endogenous and synthetic melanocortin peptides. Alpha-MSH and ACTH are endogenous nonselective agonists for MC1R, MC3R, MC4R, and MC5R. In this study, we examined the role of Phe(7) in ACTH on human (h) MC1R, MC3R, and MC4R binding and signaling. Our results indicate that substitution of Phe(7) with d-Nal(2')(7) in ACTH1-24 yields a pharmacological profile different from that for substitution of Phe(7) with d-Nal(2')(7) in MSH in hMC1R, hMC3R, and hMC4R. N-d-Nal(2')(7)-ACTH1-24 is an agonist at hMC3R and hMC4R which did not change the peptide from an agonist to an antagonist at hMC3R and hMC4R. Further experiments indicate that N-d-Nal(2')(7)-ACTH1-17 is the minimal peptide required for hMC3R and hMC4R activation. Single-amino acid substitution studies of d-Nal(2')(7)-ACTH1-17 indicate that amino acid residues 15-17 in N-d-Nal(2')(7)-ACTH1-17 are crucial for hMC3R and hMC4R activation. Substitutions of these amino acid residues reduced or abolished agonist activity at hMC3R and hMC4R. Conformational studies revealed a new beta-turn (Arg(8)-Trp(9)-Gly(10)-Lys(11)) in N-d-Nal(2')(7)-ACTH1-17, compared to the beta-turn-like structure at NDP-alpha-MSH (His(6)-d-Phe(7)-Arg(8)-Trp(9)). Our results suggest that NDP-alpha-MSH and N-d-Nal(2')(7)-ACTH1-17 do not share the same binding site; the highly basic C-terminal fragment (Lys(15)-Lys(16)-Arg(17)) of N-d-Nal(2')(7)-ACTH1-17 induced a new beta-turn, and this shift contributed the selective agonist activity at hMC3R and hMC4R.

Author information

Author/s: Yang, Yingkui (Y); Hruby, Victor J (VJ); Chen, Min (M); Crasto, Chiquito (C); Cai, Minying (M); Harmon, Carroll M (CM);

Affiliation: Department of Surgery, University of Alabama, Birmingham, Alabama 35233, USA. ying-kui.yang(-atsign-)ccc.uab.edu

Grants: DA 06248 (Agency:NIDA NIH HHS) ; DA 348900 (Agency:NIDA NIH HHS) ; R03 HD047312-01A1 (Agency:NICHD NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: Biochemistry (Biochemistry), published in United States. (Language: eng)

Reference: 2009-Oct; vol 48 (issue 41) : pp 9775-84

Dates: Created 2009/10/13; Completed 2009/11/02; Revised 2009/11/11;

PMID: 19743876, status: MEDLINE (last retrieval date: 11/12/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Adrenocorticotropic Hormone - analogs & derivatives; chemistry; metabolism Amino Acid Sequence Amino Acid Substitution Binding Sites Gene Expression Regulation Kinetics Models, Molecular

Molecular Sequence Data Peptide Fragments - chemistry Protein Conformation Receptor, Melanocortin, Type 1 - chemistry; genetics; metabolism Receptor, Melanocortin, Type 3 - chemistry; genetics; metabolism Receptor, Melanocortin, Type 4 - chemistry; genetics; metabolism Receptors, Melanocortin - chemistry; genetics; metabolism

Associated Chemicals: Peptide Fragments (0) ; Receptor, Melanocortin, Type 1 (0) ; Receptor, Melanocortin, Type 3 (0) ; Receptor, Melanocortin, Type 4 (0) ; Receptors, Melanocortin (0) ; melanocortin 5 receptor (0) ; Adrenocorticotropic Hormone (9002-60-2)

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