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3D Structure Prediction of TAS2R38 Bitter Receptors Bound to Agonists Phenylthiocarbamide (PTC) and 6-n-Propylthiouracil (PROP)

Tan, Jun and Abrol, Ravinder and Trzaskowski, Bartosz and Goddard, William A., III (2012) 3D Structure Prediction of TAS2R38 Bitter Receptors Bound to Agonists Phenylthiocarbamide (PTC) and 6-n-Propylthiouracil (PROP). Journal of Chemical Information and Modeling, 52 (7). pp. 1875-1885. ISSN 1549-9596. doi:10.1021/ci300133a.

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The G protein-coupled receptor (GPCR) TAS2R38 is a bitter taste receptor that can respond to bitter compounds such as phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP). This receptor was chosen because its four haplotypes (based on three residue site polymorphism) hTAS2R38_PAV, hTAS2R38_AVI, hTAS2R38_AAI, and hTAS2R38_PVV are known to have dramatically different responses to PTC and PROP. We aimed to identify the protein–ligand interaction features that determine whether the bitter taste signal from this receptor is sent to the cortex. To do this we predicted the 3D structures of the TAS2R38 bitter taste receptor using our new BiHelix and SuperBiHelix Monte Carlo methods (No experimental determinations of the 3D structure have been reported for any taste receptors.). We find that residue 262 (2nd position in the polymorphism) is involved in the interhelical hydrogen bond network stabilizing the GPCR structure in tasters (hTAS2R38_PAV, hTAS2R38_AAI, and hTAS2R38_PVV), while it is not in the nontaster (hTAS2R38_AVI). This suggests that the hydrogen bond interactions between TM3 and TM6 or between TM5 and TM6 may play a role in activating this GPCR. To further validate these structures, we used the DarwinDock method to predict the binding sites and 3D structures for PTC and PROP bound to hTAS2R38_PAV, hTAS2R38_AVI, hTAS2R38_AAI, and hTAS2R38_PVV, respectively. Our results show that PTC and PROP can form H-bonds with the backbone of residue 262 in the tasters (hTAS2R38_PAV, hTAS2R38_AAI, and hTAS2R38_PVV) but not in the nontaster (hTAS2R38_AVI). Thus it appears that the hydrogen bond interaction between TM3 and TM6 may activate the receptor to pass the ligand binding signal to intracellular processes and that the H-bond between agonists and residue 262 in tasters is involved in the bitter tasting. This is in agreement with experimental observations, providing validation of the predicted ligand-protein complexes and also a potential activation mechanism for the TAS2R38 receptor.

Item Type:Article
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Abrol, Ravinder0000-0001-7333-6793
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2012 American Chemical Society. Received: March 12, 2012; Published: June 1, 2012. We thank Dr. Soo-Kyung Kim for helpful discussions and Jenelle Bray for use of the BiHelix and SuperBiHelix procedures prior to publication. J.T. was financially supported by National Natural Science Foundation of China (No. 20901086) and by NIH (R01NS071112). Others were supported partially by NIH (R01NS071112) and by Sanofi-Aventis (SABER).
Funding AgencyGrant Number
National Natural Science Foundation of China20901086
Issue or Number:7
Record Number:CaltechAUTHORS:20120824-114828105
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Official Citation:3D Structure Prediction of TAS2R38 Bitter Receptors Bound to Agonists Phenylthiocarbamide (PTC) and 6-n-Propylthiouracil (PROP) Jun Tan, Ravinder Abrol, Bartosz Trzaskowski, and William A. Goddard, III Journal of Chemical Information and Modeling 2012 52 (7), 1875-1885
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:33514
Deposited By: Jason Perez
Deposited On:24 Aug 2012 20:14
Last Modified:09 Nov 2021 21:35

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