Toward G protein-coupled receptor structure-based drug design using X-ray lasers

Andrii Ishchenko, Benjamin Stauch, Gye Won Han, Alexander Batyuk, Anna Shiriaeva, Chufeng Li, Nadia Zatsepin, Uwe Weierstall, Wei Liu, Eriko Nango, Takanori Nakane, Rie Tanaka, Kensuke Tono, Yasumasa Joti, So Iwata, Isabel Moraes, Cornelius Gati, Vadim Cherezov

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


Rational structure-based drug design (SBDD) relies on the availability of a large number of co-crystal structures to map the ligand-binding pocket of the target protein and use this information for lead-compound optimization via an iterative process. While SBDD has proven successful for many drug-discovery projects, its application to G protein-coupled receptors (GPCRs) has been limited owing to extreme difficulties with their crystallization. Here, a method is presented for the rapid determination of multiple co-crystal structures for a target GPCR in complex with various ligands, taking advantage of the serial femtosecond crystallography approach, which obviates the need for large crystals and requires only submilligram quantities of purified protein. The method was applied to the human β2-adrenergic receptor, resulting in eight room-temperature co-crystal structures with six different ligands, including previously unreported structures with carvedilol and propranolol. The generality of the proposed method was tested with three other receptors. This approach has the potential to enable SBDD for GPCRs and other difficult-to-crystallize membrane proteins.

Original languageEnglish (US)
Pages (from-to)1106-1119
Number of pages14
StatePublished - Nov 1 2019


  • G protein-coupled receptors
  • X-ray free-electron lasers
  • drug discovery
  • membrane proteins
  • molecular recognition
  • protein structure
  • serial femtosecond crystallography
  • structure determination

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry
  • Materials Science(all)
  • Condensed Matter Physics


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