Conformational and topographical studies of alpha-melanotropin "message" sequence and molecular modeling of the hMC1R melanocortin receptor.

Persistent Link:
http://hdl.handle.net/10150/187200
Title:
Conformational and topographical studies of alpha-melanotropin "message" sequence and molecular modeling of the hMC1R melanocortin receptor.
Author:
Haskell-Luevano, Carrie.
Issue Date:
1995
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
The exciting and intriguing biological effects associated with amelanocyte stimulating hormone, α-MSH, have initiated a variety of studies to identify the biologically important conformations of the backbone and sidechains structures. To further investigate the topology of the critical "message" residues, several bicyclic (sidechain-to-sidechain) and x¹ restricted peptides have been synthesized and biologically examined, and selected analogues have been studied by NMR techniques and by theoretical molecular modeling studies. Bicyclic melanotropic peptides possessing the central sequence, Cys⁴-Asp⁵-His⁶-DPhe⁷-Arg⁸-Trp⁹-Cys¹⁰-Lys¹¹, exhibited nearly identical nanomolar biological potencies in the lizard skin bioassay. Molecular modeling studies suggested the hypothesis of incomplete receptor binding by either the His or Trp residue as being responsible for the decrease in potencies relative to a-MSH, and the parent monocyclic peptides from which these bicyclic peptides were designed. This hypothesis is further supported by twodimensional NMR studies of a representative bicyclic peptide, Ac-Cys⁴-Asp⁵-His⁶-DPhe⁷-Arg⁸-Trp⁹-Cys¹⁰-Lys¹¹-NH₂. Peptides synthesized to probe the topographical space of the tryptophan residue at position nine provided extraordinary results regarding the biological phenomena of prolongation. These peptides were based on the template, Ac-Nle⁴-Asp⁵-His⁶-DPhe⁷-Arg⁸-Xaa⁹-Lys¹⁰-NH₂, where Xaa consists of the four isomers of β-MeTrp, DTrp , and L- or D-TCA residues. Some of these peptides were selected for studies on the cloned hMC1 melanocortin receptor. These studies resulted in a partial hypothesis accounting for the prolonged biological activities observed in other physiological assay systems. Conformational analysis by solution 20 NMR techniques revealed similar peptide backbone secondary structure features with main differences of structure occurring in the sidechain x¹ space. The implications and results are discussed. Homology-based molecular modeling of the hMC1 melanocortin receptor was also undertaken and provided evidence for ligand-receptor interactions which are being tested by receptor mutagenesis studies. This three-dimensional computer model provides an opportunity to probe detail chemical ligand-receptor interactions and further study differences in biological activities and biological mechanisms.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Molecular biology.; Pharmaceutical chemistry.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Chemistry; Graduate College
Degree Grantor:
University of Arizona
Committee Chair:
Hruby, Victor J.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleConformational and topographical studies of alpha-melanotropin "message" sequence and molecular modeling of the hMC1R melanocortin receptor.en_US
dc.creatorHaskell-Luevano, Carrie.en_US
dc.contributor.authorHaskell-Luevano, Carrie.en_US
dc.date.issued1995en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractThe exciting and intriguing biological effects associated with amelanocyte stimulating hormone, α-MSH, have initiated a variety of studies to identify the biologically important conformations of the backbone and sidechains structures. To further investigate the topology of the critical "message" residues, several bicyclic (sidechain-to-sidechain) and x¹ restricted peptides have been synthesized and biologically examined, and selected analogues have been studied by NMR techniques and by theoretical molecular modeling studies. Bicyclic melanotropic peptides possessing the central sequence, Cys⁴-Asp⁵-His⁶-DPhe⁷-Arg⁸-Trp⁹-Cys¹⁰-Lys¹¹, exhibited nearly identical nanomolar biological potencies in the lizard skin bioassay. Molecular modeling studies suggested the hypothesis of incomplete receptor binding by either the His or Trp residue as being responsible for the decrease in potencies relative to a-MSH, and the parent monocyclic peptides from which these bicyclic peptides were designed. This hypothesis is further supported by twodimensional NMR studies of a representative bicyclic peptide, Ac-Cys⁴-Asp⁵-His⁶-DPhe⁷-Arg⁸-Trp⁹-Cys¹⁰-Lys¹¹-NH₂. Peptides synthesized to probe the topographical space of the tryptophan residue at position nine provided extraordinary results regarding the biological phenomena of prolongation. These peptides were based on the template, Ac-Nle⁴-Asp⁵-His⁶-DPhe⁷-Arg⁸-Xaa⁹-Lys¹⁰-NH₂, where Xaa consists of the four isomers of β-MeTrp, DTrp , and L- or D-TCA residues. Some of these peptides were selected for studies on the cloned hMC1 melanocortin receptor. These studies resulted in a partial hypothesis accounting for the prolonged biological activities observed in other physiological assay systems. Conformational analysis by solution 20 NMR techniques revealed similar peptide backbone secondary structure features with main differences of structure occurring in the sidechain x¹ space. The implications and results are discussed. Homology-based molecular modeling of the hMC1 melanocortin receptor was also undertaken and provided evidence for ligand-receptor interactions which are being tested by receptor mutagenesis studies. This three-dimensional computer model provides an opportunity to probe detail chemical ligand-receptor interactions and further study differences in biological activities and biological mechanisms.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectMolecular biology.en_US
dc.subjectPharmaceutical chemistry.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineChemistryen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.chairHruby, Victor J.en_US
dc.contributor.committeememberSawyer, Tomi K.en_US
dc.contributor.committeememberHadley, Mac E.en_US
dc.contributor.committeememberO'Brien, David F.en_US
dc.contributor.committeememberMiller, Walter B.en_US
dc.identifier.proquest9603348en_US
dc.identifier.oclc706711937en_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.