Strategies for the structural determination of G protein-coupled receptors: From an example of histamine H1 receptor

Mitsunori Shiroishi

研究成果: ジャーナルへの寄稿評論記事

抄録

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 dru 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.

元の言語英語
ページ(範囲)539-547
ページ数9
ジャーナルYakugaku Zasshi
133
発行部数5
DOI
出版物ステータス出版済み - 1 1 2013

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Histamine H1 Receptors
G-Protein-Coupled Receptors
Doxepin
Histamine Antagonists
Crystallization
Protein Engineering
Preclinical Drug Evaluations
Saccharomycetales
Prescription Drugs
Drug Design
Pharmaceutical Preparations
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

これを引用

Strategies for the structural determination of G protein-coupled receptors : From an example of histamine H1 receptor. / Shiroishi, Mitsunori.

:: Yakugaku Zasshi, 巻 133, 番号 5, 01.01.2013, p. 539-547.

研究成果: ジャーナルへの寄稿評論記事

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