G protein-coupled receptors (GPCRs) are versatile, ubiquitously expressed seventransmembrane domain (TMD) proteins that are conserved across the animal kingdom. In response to a strikingly diverse array of extracellular ligands such hormones, neurotransmitters, odorants, short peptides, protein ligands, and photons, GPCRs initiate a variety of intracellular signaling cascades through G protein and arrestin coupling that regulate a broad array of physiological processes including vision, olfaction, taste, neurotransmission, cellular differentiation, and immune response. The ability of GPCRs to mediate this signaling is dependent upon their TMD to undergo substantial conformational change in response to ligand binding. However, while GPCR structures determined by X-ray crystallography and cryoelectron microscopy provide invaluable temporal snapshots into the mechanisms GPCR signaling, we must understand the vast degree of conformational dynamics that exists both within and between these states with atomic-level detail to decipher the complex atomic mechanisms underlying these processes. In this dissertation, we combine molecular dynamics with structural, biochemical and biophysical studies to bridge this gap. In Chapter 1, we identify TM6 as a steric selectivity filter that facilities discrimination between Gs (stimulatory) and Gi (inhibitory) protein coupling by GPCRs. In Chapter 2, we identify a unifying sequence motif found within the C-terminal tail of most GPCRs, and many non-GPCR membrane proteins, that contributes to high affinity arrestin coupling. In Chapter 3, we uncover the chemical and molecular basis of fentanyl-mediated arrestin biased signaling for the μ-opioid receptor. The sum of these studies provides atomistic insights into the processes of ligand binding, receptor activation, and effector coupling.
|Advisor:||Xu, H. Eric|
|School:||Van Andel Research Institute|
|School Location:||United States -- Michigan|
|Source:||DAI-B 81/6(E), Dissertation Abstracts International|
|Subjects:||Biophysics, Biogeochemistry, Molecular biology|
|Keywords:||Structural dynamics, G protein-coupled receptor signaling|
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