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Download file3D Structure Prediction of TAS2R38 Bitter Receptors Bound to Agonists Phenylthiocarbamide (PTC) and 6-n-Propylthiouracil (PROP)
journal contribution
posted on 23.07.2012, 00:00 authored by Jun Tan, Ravinder Abrol, Bartosz Trzaskowski, William A. GoddardThe 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) hTAS2R38PAV, hTAS2R38AVI, hTAS2R38AAI, and hTAS2R38PVV 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 (hTAS2R38PAV, hTAS2R38AAI, and hTAS2R38PVV), while
it is not in the nontaster (hTAS2R38AVI). 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 hTAS2R38PAV, hTAS2R38AVI, hTAS2R38AAI, and hTAS2R38PVV, respectively. Our results show that PTC and PROP can form
H-bonds with the backbone of residue 262 in the tasters (hTAS2R38PAV, hTAS2R38AAI, and hTAS2R38PVV) but
not in the nontaster (hTAS2R38AVI). 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.
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Keywords
3 D structuresresidue site polymorphismhydrogen bond interactionsligand binding signalTAS 2Rtaste receptorSuperBiHelix Monte Carlo methodshTAS 2R hTAS 2R hTAS 2Rinterhelical hydrogen bond networkhTAS 2R hTAS 2RTAS 2R receptorPTCPROPTM 6TM 3hydrogen bond interactionhTAS 2RGPCR3 D Structure Predictionresidue 2623 D structure