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Introducing a New Model of Sweet Taste Receptor, a Class C G-protein Coupled Receptor (C GPCR)

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Abstract

The structure of sweet taste receptor (STR), a heterodimer of class C G-protein coupled receptors comprising T1R2 and T1R3 molecules, is still undetermined. In this study, a new enhanced model of the receptor is introduced based on the most recent templates. The improvement, stability, and reliability of the model are discussed in details. Each domain of the protein, i.e., VFTM, CR, and TMD, were separately constructed by hybrid-model construction methods and then assembled to build whole monomers. Overall, 680 ns molecular dynamics simulation was performed for the individual domains, the whole monomers and the heterodimer form of the VFTM orthosteric binding site. The latter’s structure obtained from 200 ns simulation was docked with aspartame; among various binding sites suggested by FTMAP server, the experimentally suggested binding domain in T1R2 was retrieved. Local three-dimensional structures and helices spans were evaluated and showed acceptable accordance with the template structures and secondary structure predictions. Individual domains and whole monomer structures were found stable and reliable to be used. In conclusion, several validations have shown reliability of the new and enhanced models for further molecular modeling studies on structure and function of STR and C GPCRs.

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Data Availability and Materials

The datasets generated or analyzed during the current study are not publicly available due to data privacy reasons but are available from the corresponding author on reasonable request.

Abbreviations

STR:

Human sweet taste receptor

C GPCR:

Class C of G-protein coupled receptors

7TM:

Seven transmembrane α-helices

VFTM:

Venus flytrap domain or module

CR:

Cysteine-rich domain

TMD:

Transmembrane domain

mGluR1:

Metabotropic glutamate receptor subtype 1

MD:

Molecular dynamics

N-model:

The new model introduced in the current study

R-model:

The most recent model presented

I-model:

Model represented by I-TASSER or GPCR-I-TASSER

SS:

Secondary structure

ns:

Nanoseconds

PME:

Particle mesh Ewald

RMSD:

Root mean square deviation

CA:

Carbon-alpha

SD:

Standard deviation

SDR:

Standard deviation ratio

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Acknowledgements

We thank the Non-Communicable Diseases Research Center of Endocrinology and Metabolism Population Sciences Institute and Dr. Latifeh Navidpour for allocating computational resources to help this project.

Funding

This research has been supported by the Endocrinology and Metabolism Research Institute of Tehran University of Medical Sciences.

Author Contributions

This report contains part of the results obtained from E.K.-A. Ph.D. thesis project who has done model constructions, validations, calculations and analyses, and written the manuscript text draft. A.E-H. was supervisor of the thesis, developed the initial idea and supervised the research project from data gathering to critical paper review. A.S. was advisor of the thesis and has done technical supervision of the model construction, validation, and analyses and critical paper review. B.L. was advisor of the thesis and has contributed in the idea developing and supervising project progress as an endocrine and metabolism research study. All authors have reviewed the final script and commented if necessary.

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Authors and Affiliations

  1. Biosensor Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

    Elaheh Kashani-Amin & Azadeh Ebrahim-Habibi

  2. Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

    Amirhossein Sakhteman

  3. Medicinal Chemistry and Natural Products Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Amirhossein Sakhteman

  4. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

    Bagher Larijani

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  1. Elaheh Kashani-Amin
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Correspondence to Azadeh Ebrahim-Habibi.

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Kashani-Amin, E., Sakhteman, A., Larijani, B. et al. Introducing a New Model of Sweet Taste Receptor, a Class C G-protein Coupled Receptor (C GPCR). Cell Biochem Biophys 77, 227–243 (2019). https://doi.org/10.1007/s12013-019-00872-7

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