Linked Life Data

15771429

Source:http://linkedlifedata.com/resource/pubmed/id/15771429

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2005-3-17
pubmed:abstractText
To further evaluate elements that could contribute to the 3D topographical structure of gamma-MSH, we have systematically designed a group of linear gamma-MSH analogues and evaluated their biological activities: without a N-terminal acetyl, with and without a C-terminal amide, with Nle(3), with l- or d-Phe(6) or d-Nal(2')(6), and with d-Trp(8) or d-Nal(2')(8). It was found that changing the C-terminal acid in gamma-MSH to an amide and replacing Met with Nle leads to increased binding affinities at all four subtypes of melanocortin receptors (10-100 fold). Substitution of Trp(8) with d-Nal(2')(8) and Phe(6) with d-Phe(6) in gamma-MSH-NH(2) forms a selective antagonist for the hMC3R, whereas, substitution of Phe(6) with d-Nal(2')(6) and replacing Trp(8) with d-Trp(8) at gamma-MSH-NH(2) yields a selective partial agonist for the hMC1R. Finally, substitution of His(5) with Pro(5) and Trp(8) with d-Nal(2')(8) in gamma-MSH-NH(2) leads to a highly potent and selective agonist for the hMC1R. Molecular modeling showed that, at the C-terminal of Nle(3)-gamma-MSH-NH(2), there is a reverse-turn-like structure, suggesting that there might be a secondary binding site involved in ligand-receptor interaction for gamma-MSH analogues that may explain the enhanced binding affinities of the Nle(3)-gamma-MSH-NH(2) analogues. Our results indicate that increasing the hydrophobicity and replacing Phe(6) and Trp(8) with bulkier aromatic amino acid residues is very important for selectivity of alpha-MSH/gamma-MSH hybrids for hMCRs.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
24
pubmed:volume
48
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1839-48
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:15771429-Adenylate Cyclase, pubmed-meshheading:15771429-Amino Acid Sequence, pubmed-meshheading:15771429-Binding, Competitive, pubmed-meshheading:15771429-Cell Line, pubmed-meshheading:15771429-Chromatography, High Pressure Liquid, pubmed-meshheading:15771429-Chromatography, Thin Layer, pubmed-meshheading:15771429-Humans, pubmed-meshheading:15771429-Hydrophobic and Hydrophilic Interactions, pubmed-meshheading:15771429-Ligands, pubmed-meshheading:15771429-Mass Spectrometry, pubmed-meshheading:15771429-Models, Molecular, pubmed-meshheading:15771429-Protein Structure, Secondary, pubmed-meshheading:15771429-Radioligand Assay, pubmed-meshheading:15771429-Receptors, Pituitary Hormone, pubmed-meshheading:15771429-Structure-Activity Relationship, pubmed-meshheading:15771429-alpha-MSH, pubmed-meshheading:15771429-gamma-MSH
pubmed:year
2005
pubmed:articleTitle
Novel 3D pharmacophore of alpha-MSH/gamma-MSH hybrids leads to selective human MC1R and MC3R analogues.
pubmed:affiliation
Department of Chemistry, University of Arizona, Tucson, Arizona 85721, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.