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The Development and Application of Computational Methods for the Prediction of G Protein-Coupled Receptor Structures


Bray, Jenelle Kiara (2010) The Development and Application of Computational Methods for the Prediction of G Protein-Coupled Receptor Structures. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/1655-ES74.


Computational methods for the prediction of G protein-coupled receptor (GPCR) structures were applied to serotonin receptors, and new methods were developed to predict an orphan GPCR structure. First, the MembStruk procedure was used to predict the structures of the serotonin 2b and 2c receptors. Ligand binding sites for agonists and antagonists were predicted for both receptors. In addition, the SAR data for a series of psilocybin analogs bound to serotonin 2c were predicted. There was good agreement with binding and mutagenesis experiments.

A new structure prediction procedure called SuperBiHelix was developed to predict an ensemble of low-lying structures. SuperBiHelix samples the tilt and sweep angles of the transmembrane helices along with the rotation of the helices along the helical axes. The procedure was validated on the β2-adrenergic receptor and A2A adenosine receptor crystal structures. This procedure was then used to predict the structure of GPR88, an orphan receptor. GPR88 has been identified as a novel target for psychiatric disorders. Three lipids were predicted to bind to GPR88. The head group of a lipid would bind to R113(3) and R116(3) at the extracellular side of the receptor. The lipid tail would bind in an aliphatic pocket in the TM2-TM3-TM6-TM7 region. The predicted bound complexes offer good suggestions for binding and mutagenesis experiments that could help validate the proposed structures.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:protein structure prediction; computational chemistry; drug design; GPR88; orphan receptors; serotonin receptors; GPCR
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Goddard, William A., III
Thesis Committee:
  • Barton, Jacqueline K. (chair)
  • Marcus, Rudolph A.
  • Goddard, William A., III
  • Clemons, William M.
Defense Date:10 August 2009
Record Number:CaltechETD:etd-09032009-105125
Persistent URL:
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5278
Deposited By: Jenelle Bray
Deposited On:28 Oct 2009 17:20
Last Modified:08 Nov 2019 18:06

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