help button home button Biophys. J.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Selz, K. A.
Right arrow Articles by Owens, M. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Selz, K. A.
Right arrow Articles by Owens, M. J.
Biophysical Journal 86:1308-1331 (2004)
© 2004 The Biophysical Society

Designing Human m1 Muscarinic Receptor-Targeted Hydrophobic Eigenmode Matched Peptides as Functional Modulators

Karen A. Selz * {dagger} {ddagger}, Arnold J. Mandell * {dagger} {ddagger}, Michael F. Shlesinger *, Vani Arcuragi {dagger} and Michael J. Owens {dagger}

* Cielo Institute, Asheville, North Carolina 28804; {dagger} Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322; and {ddagger} Department of Mathematical Sciences, Florida Atlantic University, Boca Raton, Florida 33136

Correspondence: Address reprint requests to Karen A. Selz, E-mail: selz{at}cieloinstitute.org.

A new proprietary de novo peptide design technique generated ten 15-residue peptides targeting and containing the leading nontransmembrane hydrophobic autocorrelation wavelengths, "modes", of the human m1 muscarinic cholinergic receptor, m1AChR. These modes were also shared by the m4AChR subtype (but not the m2, m3, or m5 subtypes) and the three-finger snake toxins that pseudoirreversibly bind m1AChR. The linear decomposition of the hydrophobically transformed m1AChR amino acid sequence yielded ordered eigenvectors of orthogonal hydrophobic variational patterns. The weighted sum of two eigenvectors formed the peptide design template. Amino acids were iteratively assigned to template positions randomly, within hydrophobic groups. One peptide demonstrated significant functional indirect agonist activity, and five produced significant positive allosteric modulation of atropine-reversible, direct-agonist-induced cellular activation in stably m1AChR-transfected Chinese hamster ovary cells, reflected in integrated extracellular acidification responses. The peptide positive allosteric ligands produced left-shifts and peptide concentration-response augmentation in integrated extracellular acidification response asymptotic sigmoidal functions and concentration-response behavior in Hill number indices of positive cooperativity. Peptide mode specificity was suggested by negative crossover experiments with human m2ACh and D2 dopamine receptors. Morlet wavelet transformation of the leading eigenvector-derived, m1AChR eigenfunctions locates seven hydrophobic transmembrane segments and suggests possible extracellular loop locations for the peptide-receptor mode-matched, modulatory hydrophobic aggregation sites.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2004 by the Biophysical Society.