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Predicted structure of fully activated human bitter taste receptor TAS2R4 complexed with G protein and agonists

Yang, Moon Young and Mafi, Amirhossein and Kim, Soo-Kyung and Goddard, William A., III and Guthrie, Brian (2021) Predicted structure of fully activated human bitter taste receptor TAS2R4 complexed with G protein and agonists. QRB Discovery, 2 . Art. No. E3. ISSN 2633-2892. https://resolver.caltech.edu/CaltechAUTHORS:20210606-012523434

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Abstract

Bitter taste is sensed by bitter taste receptors (TAS2Rs) that belong to the G protein-coupled receptor (GPCR) superfamily. In addition to bitter taste perception, TAS2Rs have been reported recently to be expressed in many extraoral tissues and are now known to be involved in health and disease. Despite important roles of TAS2Rs in biological functions and diseases, no crystal structure is available to help understand the signal transduction mechanism or to help develop selective ligands as new therapeutic targets. We report here the three-dimensional structure of the fully activated TAS2R4 human bitter taste receptor predicted using the GEnSeMBLE complete sampling method. This TAS2R4 structure is coupled to the gustducin G protein and to each of several agonists. We find that the G protein couples to TAS2R4 by forming strong salt bridges to each of the three intracellular loops, orienting the activated Gα5 helix of the Gα subunit to interact extensively with the cytoplasmic region of the activated receptor. We find that the TAS2Rs exhibit unique motifs distinct from typical Class A GPCRs, leading to a distinct activation mechanism and a less stable inactive state. This fully activated bitter taste receptor complex structure provides insight into the signal transduction mechanism and into ligand binding to TAS2Rs.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1017/qrd.2021.1DOIArticle
ORCID:
AuthorORCID
Yang, Moon Young0000-0003-4436-8010
Mafi, Amirhossein0000-0002-8366-6785
Kim, Soo-Kyung0000-0002-4498-5441
Goddard, William A., III0000-0003-0097-5716
Guthrie, Brian0000-0002-3508-4625
Additional Information:© The Author(s) 2021. Published by Cambridge University Press. This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited. Funding for this project was provided by Cargill Global Food Research. WAG thanks Dr. Fan Liu for early discussions about TAS2R4 and its activation. The computational resources for this research were provided by the Anton2 computer at the Pittsburgh National Supercomputing Center (MCB180091P) and KISTI National Supercomputing Center (KSC-2018-CHA-0049). Open Peer Review. To view the open peer review materials for this article, please visit http://doi.org/10.1017/qrd.2021.1.
Funders:
Funding AgencyGrant Number
Cargill Global Food ResearchUNSPECIFIED
Pittsburgh National Supercomputing CenterMCB180091P
KISTI National Supercomputing CenterKSC-2018-CHA-0049
Other Numbering System:
Other Numbering System NameOther Numbering System ID
WAG1465
Record Number:CaltechAUTHORS:20210606-012523434
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210606-012523434
Official Citation:Yang, M., Mafi, A., Kim, S., Goddard, W., & Guthrie, B. (2021). Predicted structure of fully activated human bitter taste receptor TAS2R4 complexed with G protein and agonists. QRB Discovery, 2, E3. doi:10.1017/qrd.2021.1
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:109406
Collection:CaltechAUTHORS
Deposited By: Donna Wrublewski
Deposited On:07 Jun 2021 17:49
Last Modified:07 Jun 2021 17:49

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