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Predicted Structure of Fully Activated Tas1R3/1R3′ Homodimer Bound to G Protein and Natural Sugars: Structural Insights into G Protein Activation by a Class C Sweet Taste Homodimer with Natural Sugars

Mafi, Amirhossein and Kim, Soo-Kyung and Chou, Keng C. and Güthrie, Brian and Goddard, William A., III (2021) Predicted Structure of Fully Activated Tas1R3/1R3′ Homodimer Bound to G Protein and Natural Sugars: Structural Insights into G Protein Activation by a Class C Sweet Taste Homodimer with Natural Sugars. Journal of the American Chemical Society, 143 (40). pp. 16824-16838. ISSN 0002-7863. doi:10.1021/jacs.1c08839. https://resolver.caltech.edu/CaltechAUTHORS:20211013-173908475

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Abstract

The Tas1R3 G protein-coupled receptor constitutes the main component of sweet taste sensory response in humans via forming a heterodimer with Tas1R2 or a homodimer with Tas1R3. The Tas1R3/1R3′ homodimer serves as a low-affinity sweet taste receptor, stimulating gustducin G protein (G_(Gust)) signaling in the presence of a high concentration of natural sugars. This provides an additional means to detect the taste of natural sugars, thereby differentiating the flavors between natural sugars and artificial sweeteners. We report here the predicted 3D structure of active state Tas1R3/1R3′ homodimer complexed with heterotrimeric GGust and sucrose. We discovered that the G_(Gust) makes ionic anchors to intracellular loops 1 and 2 of Tas1R3 while the Gα–α5 helix engages the cytoplasmic region extensively through salt bridge and hydrophobic interactions. We show that in the activation of this complex the Venus flytrap domains of the homodimer undergo a remarkable twist up to ∼100° rotation around the vertical axis to adopt a closed–closed conformation while the intracellular region relaxes to an open–open conformation. We find that binding of sucrose to the homodimer stabilizes a preactivated conformation with a largely open intracellular region that recruits and activates the G_(Gust). Upon activation, the Gα subunit spontaneously opens up the nucleotide-binding site, making nucleotide exchange facile for signaling. This activation of G_(Gust) promotes the interdomain twist of the Venus flytrap domains. These structures and transformations could potentially be a basis for the design of new sweeteners with higher activity and less unpleasant flavors.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/jacs.1c08839DOIArticle
ORCID:
AuthorORCID
Mafi, Amirhossein0000-0002-8366-6785
Kim, Soo-Kyung0000-0002-4498-5441
Chou, Keng C.0000-0002-8782-5253
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2021 American Chemical Society. Received: August 20, 2021; Published: September 29, 2021. Funding for this project was provided by Cargill Global Food Research. The Anton 2 computer time was provided by the Pittsburgh Supercomputing Center (PSC) through Grant R01GM116961 from the National Institutes of Health. The Anton 2 machine at PSC was generously made available by D.E. Shaw Research. This work also used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation Grant ACI-1548562. WAG received support from NIH (R01HL155532). The authors declare no competing financial interest.
Funders:
Funding AgencyGrant Number
Cargill Global Food ResearchUNSPECIFIED
NIHR01GM116961
NSFACI-1548562
NIHR01HL155532
Subject Keywords:Neurophysiology, Carbohydrates, Chemical structure, Conformation, Receptors
Other Numbering System:
Other Numbering System NameOther Numbering System ID
WAG1491
Issue or Number:40
DOI:10.1021/jacs.1c08839
Record Number:CaltechAUTHORS:20211013-173908475
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20211013-173908475
Official Citation:Predicted Structure of Fully Activated Tas1R3/1R3′ Homodimer Bound to G Protein and Natural Sugars: Structural Insights into G Protein Activation by a Class C Sweet Taste Homodimer with Natural Sugars. Amirhossein Mafi, Soo-Kyung Kim, Keng C. Chou, Brian Güthrie, and William A. Goddard. Journal of the American Chemical Society 2021 143 (40), 16824-16838; DOI: 10.1021/jacs.1c08839
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:111402
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:13 Oct 2021 18:34
Last Modified:19 Oct 2021 20:11

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