Capturing atomic-level mechanisms for membrane transport and signaling with biomolecular simulation
Abstract/Contents
- Abstract
- Proteins embedded in cell membranes translate a broad range of environmental cues---including the presence of nutrients, drugs, ions and photons---into molecular signals to induce appropriate cellular responses. Membrane proteins thus represent a control panel of the cell and constitute key drug targets for the treatment of a range of diseases. Designing medications to effectively modulate these proteins, however, remains exceedingly challenging and would benefit dramatically from an atomic-level understanding of how these proteins work. Here, I have used molecular dynamics (MD) simulations---which describe how every atom in a biological system evolves with high resolution in space and time---to reveal functional mechanisms for transporters and receptors, two essential classes of membrane proteins. This approach allowed us to address several long-standing questions in molecular biology. For example, we captured the complete process of substrate translocation through an alternating-access membrane transporter. These simulations, which revealed structural rearrangements in the protein that control substrate passage across the membrane as well as the driving forces underlying those transitions, suggest a structural foundation for the design of highly specific and more efficacious transporter-targeted medications. We also revealed the mechanism by which G protein--coupled receptors stimulate arrestins, intracellular regulators of cell signaling. By identifying atomic-level interactions at the GPCR--arrestin interface that drive arrestin activation, we provide a framework for designing drugs that could selectively block or stimulate arrestin signaling, thereby reducing unwanted side effects. In each study, we worked closely with our experimental collaborators to validate predictions derived from our computational results.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2019; ©2019 |
| Publication date | 2019; 2019 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Latorraca, Naomi Rose |
|---|---|
| Degree supervisor | Dror, Ron, 1975- |
| Thesis advisor | Dror, Ron, 1975- |
| Thesis advisor | Fordyce, Polly |
| Thesis advisor | Kobilka, Brian K |
| Degree committee member | Fordyce, Polly |
| Degree committee member | Kobilka, Brian K |
| Associated with | Stanford University, Biophysics Program. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Naomi R. Latorraca. |
|---|---|
| Note | Submitted to the Biophysics Program. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by Naomi Rose Latorraca
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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