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Functionally Important Aromatic–Aromatic and Sulfur−π Interactions in the D2 Dopamine Receptor

Daeffler, Kristina N.-M. and Lester, Henry A. and Dougherty, Dennis A. (2012) Functionally Important Aromatic–Aromatic and Sulfur−π Interactions in the D2 Dopamine Receptor. Journal of the American Chemical Society, 134 (36). pp. 14890-14896. ISSN 0002-7863. PMCID PMC3461201. doi:10.1021/ja304560x. https://resolver.caltech.edu/CaltechAUTHORS:20121031-153603159

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Abstract

The recently published crystal structure of the D3 dopamine receptor shows a tightly packed region of aromatic residues on helices 5 and 6 in the space bridging the binding site and what is thought to be the origin of intracellular helical motion. This highly conserved region also makes contacts with residues on helix 3, and here we use double mutant cycle analysis and unnatural amino acid mutagenesis to probe the functional role of several residues in this region of the closely related D2 dopamine receptor. Of the eight mutant pairs examined, all show significant functional coupling (Ω > 2), with the largest coupling coefficients observed between residues on different helices, C3.36/W6.48, T3.37/S5.46, and F5.47/F6.52. Additionally, three aromatic residues examined, F5.47, Y5.48, and F5.51, show consistent trends upon progressive fluorination of the aromatic side chain. These trends are indicative of a functionally important electrostatic interaction with the face of the aromatic residue examined, which is likely attributed to aromatic–aromatic interactions between residues in this microdomain. We also propose that the previously determined fluorination trend at W6.48 is likely due to a sulfur−π interaction with the side chain of C3.36. We conclude that these residues form a tightly packed structural microdomain that connects helices 3, 5, and 6, thus forming a barrier that prevents dopamine from binding further toward the intracellular surface. Upon activation, these residues likely do not change their relative conformation, but rather act to translate agonist binding at the extracellular surface into the large intracellular movements that characterize receptor activation.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/ja304560xDOIArticle
http://pubs.acs.org/doi/abs/10.1021/ja304560xPublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461201PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2012 American Chemical Society. Received: May 10, 2012; Published: August 16, 2012; Published In Issue: September 12, 2012; Article ASAP: August 31, 2012. This work was supported by the National Institutes of Health grant GM081662. The authors declare no competing financial interest.
Funders:
Funding AgencyGrant Number
NIHGM081662
Issue or Number:36
PubMed Central ID:PMC3461201
DOI:10.1021/ja304560x
Record Number:CaltechAUTHORS:20121031-153603159
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20121031-153603159
Official Citation:Functionally Important Aromatic–Aromatic and Sulfur−π Interactions in the D2 Dopamine Receptor Kristina N.-M. Daeffler, Henry A. Lester, and Dennis A. Dougherty Journal of the American Chemical Society 2012 134 (36), 14890-14896
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:35220
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:01 Nov 2012 18:23
Last Modified:09 Nov 2021 23:13

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