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Understanding the structural and functional differences between mouse thyrotropin-releasing hormone receptors 1 and 2

Authors

  • Francesca Deflorian,

    1. Laboratory of Biological Modeling, National Institute of Diabetes and Digestive, and Kidney Diseases, NIH, Bethesda, Maryland 20892-5646
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  • Stanislav Engel,

    1. Clinical Endocrinology Branch, National Institute of Diabetes and Digestive, and Kidney Diseases, NIH, Bethesda, Maryland 20892-5646
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  • Anny-Odile Colson,

    1. Laboratory of Biological Modeling, National Institute of Diabetes and Digestive, and Kidney Diseases, NIH, Bethesda, Maryland 20892-5646
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  • Bruce M. Raaka,

    1. Clinical Endocrinology Branch, National Institute of Diabetes and Digestive, and Kidney Diseases, NIH, Bethesda, Maryland 20892-5646
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  • Marvin C. Gershengorn,

    Corresponding author
    1. Clinical Endocrinology Branch, National Institute of Diabetes and Digestive, and Kidney Diseases, NIH, Bethesda, Maryland 20892-5646
    • Clinical Endocrinology Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, NIH, Bethesda, MD 20892-5646
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  • Stefano Costanzi

    Corresponding author
    1. Laboratory of Biological Modeling, National Institute of Diabetes and Digestive, and Kidney Diseases, NIH, Bethesda, Maryland 20892-5646
    • Laboratory of Biological Modeling, National Institute of Diabetes, Digestive, and Kidney Diseases, NIH, Bethesda, MD 20892-5646
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  • This article is a US Government work and, as such, is in the public domain in the United States of America

Abstract

Multiple computational methods have been employed in a comparative study of thyrotropin-releasing hormone receptors 1 and 2 (TRH-R1 and TRH-R2) to explore the structural bases for the different functional properties of these G protein-coupled receptors. Three-dimensional models of both murine TRH receptors have been built and optimized by means of homology modeling based on the crystal structure of bovine rhodopsin, molecular dynamics simulations, and energy minimizations in a membrane-aqueous environment. The comparison between the two models showed a correlation between the higher flexibility and higher basal activity of TRH-R2 versus the lesser flexibility and lower basal activity of TRH-R1 and supported the involvement of the highly conserved W6.48 in the signaling process. A correlation between the level of basal activity and conformational changes of TM5 was detected also. Comparison between models of the wild type receptors and their W6.48A mutants, which have reversed basal activities compared with their respective wild types, further supported these correlations. A flexible molecular docking procedure revealed that TRH establishes a direct interaction with W6.48 in TRH-R2 but not in TRH-R1. We designed and performed new mutagenesis experiments that strongly supported these observations. Proteins 2008; 71:783–794. Published 2007 Wiley-Liss, Inc.

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