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IUCrJ. 2019 Oct 24;6(Pt 6):1106-1119. doi: 10.1107/S2052252519013137. eCollection 2019 Nov 1.

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

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Bridge Institute, Departments of Chemistry and Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.
Department of Physics, Arizona State University, Tempe, AZ 85287, USA.
Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
School of Molecular Sciences and Biodesign Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA.
RIKEN SPring-8 Center, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5148, Japan.
Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 2-11-16 Yayoi, Bunkyo, Tokyo 113-0032, Japan.
Japan Synchrotron Radiation Research Institute, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5198, Japan.
National Physical Laboratory, Hampton Road, Teddington TW11 0LW, England.
Research Complex at Harwell, Rutherford Appleton Laboratory, Harwell Science and Innovation Campus, Didcot OX11 0FA, England.
Department of Structural Biology, Stanford University, Stanford, CA 94305, USA.
Biosciences Division, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.


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.


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

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