Abstract
Beyond the targeting of E3 ubiquitin ligases to inhibit protein homeostasis, E3 ligase binders can be repurposed as targeted protein degraders (PROTACs or molecular glues). We sought to identify new binders of the VHL E3 ligase by biophysical fragment-based screening followed by X-ray crystallographic soaking. We identified fragments binding at the ElonginC:Cullin2 interface and a new cryptic pocket in VHL, along with other potential ligandable sites predicted computationally and found to bind solvent molecules in crystal structures. The elucidated interactions provide starting points for future ligand development.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Binding Sites
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Crystallography, X-Ray
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Drug Evaluation, Preclinical / methods*
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Elongin / chemistry
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Elongin / metabolism
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Fluorometry / methods
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Humans
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Ligands
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Magnetic Resonance Spectroscopy
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Multiprotein Complexes / chemistry*
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Multiprotein Complexes / metabolism
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Polycythemia / genetics
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology
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Ubiquitin-Protein Ligases / chemistry
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Ubiquitin-Protein Ligases / metabolism*
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Von Hippel-Lindau Tumor Suppressor Protein / chemistry
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism*
Substances
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ELOB protein, human
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ELOC protein, human
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Elongin
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Ligands
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Multiprotein Complexes
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Small Molecule Libraries
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein
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VHL protein, human