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Structures and Agonist Binding Sites of Bitter Taste Receptor TAS2R5 Complexed with Gi Protein and Validated against Experiment

Yang, Moon Young and Kim, Soo-Kyung and Kim, Donghwa and Liggett, Stephen B. and Goddard, William A., III (2021) Structures and Agonist Binding Sites of Bitter Taste Receptor TAS2R5 Complexed with Gi Protein and Validated against Experiment. Journal of Physical Chemistry Letters, 12 (38). pp. 9293-9300. ISSN 1948-7185. doi:10.1021/acs.jpclett.1c02162. https://resolver.caltech.edu/CaltechAUTHORS:20211008-224623544

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Abstract

Bitter taste receptors (TAS2Rs) function in taste perception, but are also expressed in many extraoral tissues, presenting attractive therapeutic targets. TAS2R5s expressed on human airway smooth muscle cells can induce bronchodilation for treating asthma and other obstructive diseases. But TAS2R5s display low agonist affinity and the lack of a 3D structure has hindered efforts to design more active ligands. We report the structure of the activated TAS2R5 coupled to the Gi protein and bound to each of 19 agonists, using computational approaches. These agonists bind to two polar residues in TM3 that are unique for TAS2R5 among 25 TAS2R subtypes. Our predicted results correlate well with experimental results of agonist-receptor signaling coefficients, providing validation of the predicted structure. These results provide highly specific data on how agonists activate TAS2R5, how modifications of ligand structure alter receptor activation, and a guide to structure-based drug design.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acs.jpclett.1c02162DOIArticle
ORCID:
AuthorORCID
Yang, Moon Young0000-0003-4436-8010
Kim, Soo-Kyung0000-0002-4498-5441
Liggett, Stephen B.0000-0002-0128-3669
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2021 American Chemical Society. Received 4 July 2021. Accepted 31 August 2021. Published online 20 September 2021. Published in issue 30 September 2021. This research was supported by grants from the NIH (1R01HL155532 and P01HL114471). We thank Dr. Amirhossein Mafi for helpful discussions. The computational resource for this research was provided by KISTI National Supercomputing Center (KSC-2018-CHA-0049). The authors declare no competing financial interest.
Funders:
Funding AgencyGrant Number
NIH1R01HL155532
NIHP01HL114471
KISTI National Supercomputing CenterKSC-2018-CHA-0049
Subject Keywords:Peptides and proteins, Agonists, Ligands, Chemical structure, Receptors
Other Numbering System:
Other Numbering System NameOther Numbering System ID
WAG1489
Issue or Number:38
DOI:10.1021/acs.jpclett.1c02162
Record Number:CaltechAUTHORS:20211008-224623544
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20211008-224623544
Official Citation:Structures and Agonist Binding Sites of Bitter Taste Receptor TAS2R5 Complexed with Gi Protein and Validated against Experiment Moon Young Yang, Soo-Kyung Kim, Donghwa Kim, Stephen B. Liggett, and William A. Goddard The Journal of Physical Chemistry Letters 2021 12 (38), 9293-9300 DOI: 10.1021/acs.jpclett.1c02162
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:111326
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:12 Oct 2021 14:20
Last Modified:19 Oct 2021 19:06

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