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Adrenergic receptors : model systems for investigation of G-protein coupled receptor structure and function

Citation

Wiencko, Heather L (2009) Adrenergic receptors : model systems for investigation of G-protein coupled receptor structure and function. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechETD:etd-05292009-094239

Abstract

Membrane proteins mediate intercellular communication, resulting in changes in the membrane and within the cell itself. One superfamily of integral membrane proteins, G-protein coupled receptors (GPCRs), are responsible for a vast diversity of processes. Their conformational flexibility and membrane environment pose challenges for direct structural characterization, and to date only five of the more than 1,000 known GPCRs have been characterized by high-resolution crystallography.

The nine adrenergic GPCRs mediate the stress response throughout the body, and are implicated in diseases including hypertension and asthma. While they are among the best studied families of GPCRs, much remains to be learned about selectivity and activation. The first section of this work describes the ab initio structure prediction of the turkey beta-1 receptor and validation using a series of stabilizing mutations. This work preceded the currently available turkey beta-1 structure but shows good agreement, especially in the binding site. It validates the latest methods developed for GPCR structure prediction, emphasizes the role of a neutral charge scheme in energy determination, and explores a structure validation strategy based on stabilizing mutations rather than ligand docking. The next section uses the experimental beta-1 crystal structure as a starting point for nanosecond timescale molecular dynamics, exploring the roles of ligand binding in helix movement that contribute to the transition to an active state. These simulations reveal the early steps in receptor activation, beginning with tilting motions of transmembrane helices 5 and 6 and movement of transmembrane helix 1 closer into the protein core. The last section presents homology models of the human adrenergic receptors for which there are not yet crystal structures. The receptors most closely related to the target structures show the best results, while the less related ones will require further refinement. The best structures provide insight into the binding site of subtype selective antagonists, and can serve as the foundation for future studies. Over the course of these explorations, new subtleties in adrenergic structure have been illuminated, and may drive further exploration into selective binding and the activation mechanism of these and other receptors.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:binding site prediction; computational structure prediction; drug design; GPCR; homology modeling; ligand binding site; ligand docking; modeling; molecular dynamics; protein modeling; protein structure; structure prediction; structure validation
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Restricted to Caltech community only
Research Advisor(s):
  • Goddard, William A., III
Thesis Committee:
  • Dervan, Peter B. (chair)
  • Rees, Douglas C.
  • Gray, Harry B.
  • Heath, James R.
  • Goddard, William A., III
Defense Date:18 May 2009
Author Email:hlw (AT) wag.caltech.edu
Record Number:CaltechETD:etd-05292009-094239
Persistent URL:http://resolver.caltech.edu/CaltechETD:etd-05292009-094239
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:2268
Collection:CaltechTHESIS
Deposited By: Imported from ETD-db
Deposited On:29 May 2009
Last Modified:26 Dec 2012 02:49

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