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Dissecting the Functions of Conserved Prolines within Transmembrane Helices of the D2 Dopamine Receptor

Van Arnam, Ethan B. and Lester, Henry A. and Dougherty, Dennis A. (2011) Dissecting the Functions of Conserved Prolines within Transmembrane Helices of the D2 Dopamine Receptor. ACS Chemical Biology, 6 (10). pp. 1063-1068. ISSN 1554-8929. https://resolver.caltech.edu/CaltechAUTHORS:20111116-105837023

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Abstract

G protein-coupled receptors (GPCRs) contain a number of conserved proline residues in their transmembrane helices, and it is generally assumed these play important functional and/or structural roles. Here we use unnatural amino acid mutagenesis, employing α-hydroxy acids and proline analogues, to examine the functional roles of five proline residues in the transmembrane helices of the D2 dopamine receptor. The well-known tendency of proline to disrupt helical structure is important at all sites, while we find no evidence for a functional role for backbone amide cis–trans isomerization, another feature associated with proline. At most proline sites, the loss of the backbone NH is sufficient to explain the role of the proline. However, at one site, P210^(5.50), a substituent on the backbone N appears to be essential for proper function. Interestingly, the pattern in functional consequences that we see is mirrored in the pattern of structural distortions seen in recent GPCR crystal structures.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/cb200153gDOIArticle
http://pubs.acs.org/doi/full/10.1021/cb200153gPublisherArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2011 American Chemical Society. Received: May 13, 2011. Accepted: July 21, 2011. Publication Date (Web): July 21, 2011. This work was supported by National Institutes of Health grant GM081662.
Funders:
Funding AgencyGrant Number
NIHGM081662
Issue or Number:10
Record Number:CaltechAUTHORS:20111116-105837023
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20111116-105837023
Official Citation:Dissecting the Functions of Conserved Prolines within Transmembrane Helices of the D2 Dopamine Receptor Ethan B. Van Arnam, Henry A. Lester, and Dennis A. Dougherty ACS Chemical Biology 2011 6 (10), 1063-1068
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:27806
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:16 Nov 2011 21:31
Last Modified:03 Oct 2019 03:26

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