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

Mitsunori Shiroishi

Research output: Contribution to journalReview article

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 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.

Original languageEnglish
Pages (from-to)539-547
Number of pages9
JournalYakugaku Zasshi
Volume133
Issue number5
DOIs
Publication statusPublished - 2013

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Fingerprint Dive into the research topics of 'Strategies for the structural determination of G protein-coupled receptors: From an example of histamine H<sub>1</sub> receptor'. Together they form a unique fingerprint.

  • Cite this