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Title page for ETD etd-07172013-164828


Type of Document Dissertation
Author Nguyen, Elizabeth Dong
Author's Email Address elizdong@gmail.com
URN etd-07172013-164828
Title Structural Studies of the Interaction between mGlu5 and Allosteric Modulators
Degree PhD
Department Chemical and Physical Biology
Advisory Committee
Advisor Name Title
Walter J. Chazin, Ph.D. Committee Chair
David L. Tabb, Ph.D. Committee Member
P. Jeffrey Conn, Ph.D. Committee Member
Terry P. Lybrand, Ph.D. Committee Member
Keywords
  • ligand docking
  • GPCR
  • schizophrenia
  • computational structural biology
  • protein structure prediction
Date of Defense 2013-06-17
Availability unrestricted
Abstract
The metabotropic glutamate receptor subtype 5 (mGlu5), a class C G-protein coupled receptor (GPCR), is involved in cognitive function through diverse signaling pathways that modulate synaptic plasticity. Modulators of mGlu5 hold exciting potential for the development of novel treatment strategies that target disorders disrupting cognitive function. Because the orthosteric binding site is well conserved between all subtypes of mGlus, an approach to selectively targeting mGlu5 is to identify ligands with allosteric binding sites. Identifying specific residues on mGlu5 that contact these allosteric modulators would provide a deeper understanding of the binding interaction and aid in the development of such therapeutic compounds. While there is no high resolution structure of the transmembrane region of mGlu5, comparative structural models of mGlu5 have been shown to accurately predict critical residues for allosteric modulation. As part of this thesis work, methods for the docking of ligands into computational models of GPCRs was developed, validated and applied to mGlu5 to characterize the interaction between the receptor and allosteric modulators and allow for a deeper understanding of the residues important to allosteric ligand-receptor interactions.
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