Strategies for the Structural Determination of G Protein-coupled Receptors: From an Example of Histamine H<sub>1</sub> Receptor

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  • G タンパク質共役型受容体の構造解析に向けた戦略 ～ヒスタミンH<sub>1</sub>受容体を例に～
  • Gタンパク質共役型受容体の構造解析に向けた戦略 : ヒスタミンH₁受容体を例に
  • Gタンパクシツ キョウヤクガタ ジュヨウタイ ノ コウゾウ カイセキ ニ ムケタ センリャク : ヒスタミン H ₁ ジュヨウタイ オ レイ ニ

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Abstract

  G protein-coupled receptors (GPCRs) are major therapeutic drug targets and represent more than 30% of the market share of all prescription drugs. The high-resolution three-dimensional structures of the target receptors provide good initial models for structure-based approaches to drug screening and drug design, which are considered to accelerate drug discovery. However, significant bottlenecks at the expression, purification and crystallization stages of structure determination of GPCRs have existed. Here, we review recent techniques for the determination of GPCR structures. In particular, we focus on the protein engineering techniques that have been used to overcome bottlenecks in expression/purification and crystallization, including our development of a platform using budding yeast for the rapid construction and evaluation of GPCR variants for structural studies. We also present our success in determining the crystal structure of the histamine H1 receptor (H1R) in complex with doxepin, an inverse agonist antihistamine. The H1R structure revealed the low selectivity of doxepin to aminergic receptors and provides key information that should aid the development of highly selective antihistamines.<br>

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 133 (5), 539-547, 2013-05-01

    The Pharmaceutical Society of Japan

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