Structural dynamics of G protein-coupled receptor activation
Abstract/Contents
- Abstract
- G protein-coupled receptors (GPCRs) are transmembrane proteins that mediate complex cellular responses to hormones and neurotransmitters. GPCRs can activate many signaling pathways, either through interactions with heterotrimeric G proteins or through G protein-independent pathways. The function of GPCRs can be modulated by a variety of ligands with a broad range of efficacies, often in a signaling pathway specific manner. Understanding this complex signaling behavior requires insight into the molecular mechanisms of GPCR function. Recent advances in GPCR crystallography have elucidated the structure of a few prototypical receptors, rhodopsin and the β2 adrenergic receptor (β2AR), in both inactive and active conformations. Here, I describe my efforts to understand the structure and dynamics of GPCR activation. To extend the available model systems beyond rhodopsin and the β2AR, I describe the inactive-state structures of the μ and δ opioid receptors as well as a recently determined structure of an activated, agonist-bound μ opioid receptor. I also describe active state structures of the M2 muscarinic receptor and higher resolution structures of the activated β2AR bound its endogenous hormone adrenaline. Finally, I describe a set of studies utilizing 19F-fluorine nuclear magnetic resonance (NMR) and double electron-electron resonance spectroscopy to assess the conformational dynamics of β2AR activation. Together, these studies establish the conformational complexity associated with GPCR activation and how this structural plasticity is likely responsible for the broad versatility of GPCR signaling.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2016 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Manglik, Aashish |
|---|---|
| Associated with | Stanford University, Biophysics Program. |
| Primary advisor | Kobilka, Brian K |
| Thesis advisor | Kobilka, Brian K |
| Thesis advisor | Feng, Liang, 1963- |
| Thesis advisor | Pande, Vijay |
| Thesis advisor | Weis, William I |
| Advisor | Feng, Liang, 1963- |
| Advisor | Pande, Vijay |
| Advisor | Weis, William I |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Aashish Manglik. |
|---|---|
| Note | Submitted to the Program in Biophysics. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2016. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2016 by Aashish Manglik
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...