Activation mechanism of the G protein-coupled sweet receptor heterodimer with sweeteners and allosteric agonists.
Proc Natl Acad Sci U S A
; 114(10): 2568-2573, 2017 03 07.
Article
en En
| MEDLINE
| ID: mdl-28228527
ABSTRACT
The sweet taste in humans is mediated by the TAS1R2/TAS1R3 G protein-coupled receptor (GPCR), which belongs to the class C family that also includes the metabotropic glutamate and γ-aminobutyric acid receptors. We report here the predicted 3D structure of the full-length TAS1R2/TAS1R3 heterodimer, including the Venus Flytrap Domains (VFDs) [in the closed-open (co) active conformation], the cysteine-rich domains (CRDs), and the transmembrane domains (TMDs) at the TM56/TM56 interface. We observe that binding of agonists to VFD2 of TAS1R2 leads to major conformational changes to form a TM6/TM6 interface between TMDs of TAS1R2 and TAS1R3, which is consistent with the activation process observed biophysically on the metabotropic glutamate receptor 2 homodimer. We find that the initial effect of the agonist is to pull the bottom part of VFD3/TAS1R3 toward the bottom part of VFD2/TAS1R2 by â¼6 Å and that these changes get transmitted from VFD2 of TAS1R2 (where agonists bind) through the VFD3 and the CRD3 to the TMD3 of TAS1R3 (which couples to the G protein). These structural transformations provide a detailed atomistic mechanism for the activation process in GPCR, providing insights and structural details that can now be validated through mutation experiments.
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Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Conformación Proteica
/
Receptores Acoplados a Proteínas G
/
Percepción del Gusto
Límite:
Animals
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Humans
Idioma:
En
Año:
2017
Tipo del documento:
Article