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Dissertation
ROLE OF THE MEMBRANE LIPIDS IN THE MOLECULAR RECOGNITION OF GPCRS
Washington State University
Doctor of Philosophy (PhD), Washington State University
01/2022
DOI:
https://doi.org/10.7273/000004407
Handle:
https://hdl.handle.net/2376/125131
Abstract
Integral membrane proteins constitute approximately one-third of all proteins expressed in biological organisms and are involved in numerous cellular processes. G protein-coupled receptors (GPCRs) and ion channels constitute 31% of all human therapeutic targets, through which >50% of the marketed small-molecule drugs exert their pharmacological effects. Cell membranes have been known to serve as essential structural media for the proper localization, structure, and function of these protein targets. However, a growing body of evidence shows that membrane lipids play more sophisticated roles. Recent biophysical and computational studies reveal that lipophilic and amphiphilic ligands gain access to their protein targets by first partitioning into the surrounding membrane and then laterally diffuse through the membrane. The structural organization and constraints of the bilayer, including lipid composition, appear to play critical roles in directing ligands to a specific depth within the bilayer and in “pre-organizing” them in an optimal orientation to facilitate receptor binding. Remarkably, several crystal structures of GPCRs and ligand-gated ion channels bound to their ligands offer details on allosteric binding sites at lipid-transmembrane helix interfaces that can be accessed only via lipid-mediated paths. There is a critical gap in the fundamental knowledge of how interactions among these species affect access, binding kinetics, and affinities of drugs to lipid-exposed transmembrane sites. This thesis embodies important work that lays the groundwork for establishing structure-membrane interaction relationships (SMIR) of drugs to characterize the complex interplay between lipids, protein, and ligand molecules to better understand casual and mechanistic relationships. Importantly, an insightful SMIR has been elucidated for the three most commonly used β2-adrenergic receptor agonists, illustrating the role of membrane lipids in affecting their onset and duration of action. Also, a transmembrane allosteric binding site has been characterized for the µ-opioid receptors, and a drug-discovery platform has been established to identify high-affinity allosteric modulators as potential therapeutics with a better safety profile in the treatment of pain. The knowledge gained through this body of work is broadly generalizable to ligands targeting any integral membrane proteins and will greatly facilitate the rational design of drugs directed at a variety of important therapeutic targets.
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Details
- Title
- ROLE OF THE MEMBRANE LIPIDS IN THE MOLECULAR RECOGNITION OF GPCRS
- Creators
- Christopher Tytus Szlenk
- Contributors
- Senthil Natesan (Advisor)Kathryn Meier (Committee Member)Michael Gibson (Committee Member)Zhaokang Cheng (Committee Member)Jean-Baptiste Roullet (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- College of Pharmacy and Pharmaceutical Sciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 202
- Identifiers
- 99900883238001842
- Language
- English
- Resource Type
- Dissertation