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Structure-function studies of nicotinic acetylcholine receptors using unnatural amino acids and synthetic agonist analogs

Citation

Blum, Angela Patricia (2012) Structure-function studies of nicotinic acetylcholine receptors using unnatural amino acids and synthetic agonist analogs. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:11042011-173102026

Abstract

This dissertation primarily describes structure-function studies of the prototypical Cys-loop ligand-gated ion channel, the nicotinic acetylcholine receptors (nAChRs).

Agonists that bind nAChRs, including acetylcholine, nicotine, and the smoking cessation drug varenicline, share one of the longest-known, best-studied pharmacophores, consisting of a cationic N and a hydrogen bond acceptor. A major theme of this thesis is concerned with defining the nAChR residues that bind the nicotinic pharmacophore. Chapters 2 and 3 establish that a hydrogen bond links the pharmacophore’s hydrogen bond acceptor to a backbone NH in the protein. The establishment of this interaction, and the disproval of other predicted interactions, represents the completion of the nicotinic pharmacophore binding model. Chapter 4 uses this model to characterize how the nAChR differentiates between stereoisomers of an agonist.

Chapter 5 describes functional studies of a vicinal disulfide that has played a pivotal role in a number of pioneering studies of nAChRs. Despite its historical importance, the functional role of this disulfide has not been defined. We identify a speculative role for the vicinal disulfide that involves the formation of a functionally important network of hydrogen bonds.

Chapter 6 outlines three strategies for the photochemical cleavage of protein and peptide backbones using unnatural amino acids. One of these strategies is based on a selenide-mediated cleavage of a backbone ester moiety. Model studies establish the viability of this chemistry and suggest that it could be a useful tool for protein structure-function studies.

Chapter 7 concerns preliminary work from a collaboration with laboratories from USC and Caltech that is aimed at developing small-molecule treatments for vision loss associated with photoreceptor degeneration. The initial goal of this project is to develop a photosensitive small molecule that can activate a voltage-gated potassium channel.

The final chapter discusses work that was done in the Grubbs lab at Caltech in which a strategy for preparing N-heterocyclic carbene-containing metal complexes was developed.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:nicotinic acetylcholine receptor; nicotine, pharmacophore, vicinal disulfide
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Dougherty, Dennis A.
Thesis Committee:
  • Grubbs, Robert H. (chair)
  • Dervan, Peter B.
  • Barton, Jacqueline K.
  • Dougherty, Dennis A.
Defense Date:11 September 2011
Record Number:CaltechTHESIS:11042011-173102026
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:11042011-173102026
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:6728
Collection:CaltechTHESIS
Deposited By: Angela Blum
Deposited On:22 Nov 2011 17:09
Last Modified:24 Sep 2014 16:49

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