Department of Biochemistry, University of Washington, Seattle, United States
Per J Greisen
Department of Biochemistry, University of Washington, Seattle, United States
Kevin J Morey
Department of Biology, Colorado State University, Fort Collins, United States
Mauricio S Antunes
Department of Biology, Colorado State University, Fort Collins, United States
David La
Department of Biochemistry, University of Washington, Seattle, United States
Banumathi Sankaran
Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, United States
Luc Reymond
Ecole Polytechnique Fédérale de Lausanne, Institute of Chemical Sciences and Engineering, Lausanne, Switzerland; Department of Chemical Biology, Max-Planck-Institute for Medical Research, Heidelberg, Germany
Kai Johnsson
Ecole Polytechnique Fédérale de Lausanne, Institute of Chemical Sciences and Engineering, Lausanne, Switzerland; Department of Chemical Biology, Max-Planck-Institute for Medical Research, Heidelberg, Germany
June I Medford
Department of Biology, Colorado State University, Fort Collins, United States
Department of Biochemistry, University of Washington, Seattle, United States; Howard Hughes Medical Institute, University of Washington, Seattle, United States
We describe the computational design of proteins that bind the potent analgesic fentanyl. Our approach employs a fast docking algorithm to find shape complementary ligand placement in protein scaffolds, followed by design of the surrounding residues to optimize binding affinity. Co-crystal structures of the highest affinity binder reveal a highly preorganized binding site, and an overall architecture and ligand placement in close agreement with the design model. We use the designs to generate plant sensors for fentanyl by coupling ligand binding to design stability. The method should be generally useful for detecting toxic hydrophobic compounds in the environment.
