Ligand and Target Discovery by Fragment-Based Screening in Human Cells.
- Parker CG Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: cparker@scripps.edu.
- Galmozzi A Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
- Wang Y Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
- Correia BE École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
- Sasaki K Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
- Joslyn CM Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
- Kim AS Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
- Cavallaro CL Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08648, USA.
- Lawrence RM Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08648, USA.
- Johnson SR Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08648, USA.
- Narvaiza I The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
- Saez E Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: esaez@scripps.edu.
- Cravatt BF Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: cravatt@scripps.edu.
- 2017-01-24
Published in:
- Cell. - 2017
FBLD
PGRMC2
adipogenesis
chemical probes
chemical proteomics
fragment-based ligand discovery
ligands
mass spectrometry
phenotypic screening
photoreactivity
Adipocytes
Cell Differentiation
Crystallography, X-Ray
Drug Discovery
High-Throughput Screening Assays
Humans
Hydrolases
Ligands
Membrane Proteins
Oxidoreductases
Protein Binding
Proteomics
Receptors, Progesterone
Small Molecule Libraries
English
Advances in the synthesis and screening of small-molecule libraries have accelerated the discovery of chemical probes for studying biological processes. Still, only a small fraction of the human proteome has chemical ligands. Here, we describe a platform that marries fragment-based ligand discovery with quantitative chemical proteomics to map thousands of reversible small molecule-protein interactions directly in human cells, many of which can be site-specifically determined. We show that fragment hits can be advanced to furnish selective ligands that affect the activity of proteins heretofore lacking chemical probes. We further combine fragment-based chemical proteomics with phenotypic screening to identify small molecules that promote adipocyte differentiation by engaging the poorly characterized membrane protein PGRMC2. Fragment-based screening in human cells thus provides an extensive proteome-wide map of protein ligandability and facilitates the coordinated discovery of bioactive small molecules and their molecular targets.
- Language
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- English
- Open access status
- bronze
- Identifiers
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- DOI 10.1016/j.cell.2016.12.029
- PMID 28111073
- Persistent URL
- https://folia.unifr.ch/global/documents/97377
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