CaltechAUTHORS
  A Caltech Library Service

Characterizing and predicting the functional and conformational diversity of seven-transmembrane proteins

Abrol, Ravinder and Kim, Soo-Kyung and Bray, Jenelle K. and Griffith, Adam R. and Goddard, William A., III (2011) Characterizing and predicting the functional and conformational diversity of seven-transmembrane proteins. Methods, 55 (4). pp. 405-414. ISSN 1046-2023. PMCID PMC3286597. https://resolver.caltech.edu/CaltechAUTHORS:20120227-133905808

[img] PDF - Accepted Version
See Usage Policy.

2419Kb

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20120227-133905808

Abstract

The activation of seven-transmembrane receptors (7TMRs) allows cells to sense their environment and convert extracellular signals (like hormone binding) into intracellular signals (through G protein-coupled and/or β arrestin-coupled pathways). A single 7TMR is capable of transducing a wide spectrum of physiological responses inside a cell by coupling to these pathways. This intracellular pleiotropic action is enabled by multiple conformations exhibited by these receptors. Developments in membrane protein structure determination technologies have led to a rapid increase in crystal structures for many 7TMRs. Majority of these receptors have been crystallized in their inactive conformation and, for some, one of the many active conformations has also been crystallized. Given the topological constraints of a lipid bilayer that results in a single fold of seven almost parallel TM helices connected by mostly unstructured loops, these structures exhibit a diversity of conformations not only across the receptors but also across the different functional forms for receptors with structures for one of the functionally active conformations. Here we present a method to characterize this conformational diversity in terms of transmembrane helix topology (TMHTOP) parameters and how to use these helix orientation parameters to predict functionally-distinct multiple conformations for these receptors. The TMHTOP parameters enable a quantification of the structural changes that underlie 7TMR activation and also sheds a unique mechanistic light on the pleiotropic nature of these receptors. It provides a common language to describe the 7TMR activation mechanisms as well as differences across many receptors in terms of visually intuitive structural parameters. Protein structure prediction methods can use these parameters to describe 7TMR conformational ensembles, which coupled to experimental data can be used to develop testable hypotheses for the structural basis of 7TMR functions.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.ymeth.2011.12.005 DOIArticle
http://www.sciencedirect.com/science/article/pii/S1046202311002477PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286597PubMed CentralArticle
ORCID:
AuthorORCID
Abrol, Ravinder0000-0001-7333-6793
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2011 Elsevier Inc. Available online 17 December 2011. This work was funded by gifts to the Materials and Process Simulation Center at Caltech, and in part by the NIH Grant 5R21MH073910.
Funders:
Funding AgencyGrant Number
NIH5R21MH073910
Subject Keywords:G protein-coupled receptors; GPCRs; Conformational ensemble; Functional selectivity; Protein structure prediction; Transmembrane helix topology
Other Numbering System:
Other Numbering System NameOther Numbering System ID
WAG0959
Issue or Number:4
PubMed Central ID:PMC3286597
Record Number:CaltechAUTHORS:20120227-133905808
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20120227-133905808
Official Citation:Ravinder Abrol, Soo-Kyung Kim, Jenelle K. Bray, Adam R. Griffith, William A. Goddard III, Characterizing and predicting the functional and conformational diversity of seven-transmembrane proteins, Methods, Volume 55, Issue 4, December 2011, Pages 405-414, ISSN 1046-2023, 10.1016/j.ymeth.2011.12.005.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:29490
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:28 Feb 2012 23:54
Last Modified:03 Oct 2019 03:41

Repository Staff Only: item control page