Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN

The small molecules thalidomide, lenalidomide, and pomalidomide induce the ubiquitination and proteasomal degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) by recruiting a Cys -His (C2H2) zinc finger domain to Cereblon (CRBN), the substrate receptor of the CRL4 E3 ubiquitin...

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Published in:Science (American Association for the Advancement of Science) 2018-11, Vol.362 (6414)
Main Authors: Sievers, Quinlan L, Petzold, Georg, Bunker, Richard D, Renneville, Aline, Słabicki, Mikołaj, Liddicoat, Brian J, Abdulrahman, Wassim, Mikkelsen, Tarjei, Ebert, Benjamin L, Thomä, Nicolas H
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing
Amino Acid Sequence
Amino acids
Analogs
Binding
Biochemical analysis
Blood cancer
Cancer
Catalysis
Computation
Computer applications
Conserved sequence
Crystal structure
CYS2-HIS2 Zinc Fingers
Degradation
Docking
Domains
Drug dependence
Drug development
Drugs
Fingers
Genomes
HEK293 Cells
Humans
Ikaros protein
Ikaros Transcription Factor - metabolism
Lenalidomide - pharmacology
Multiple myeloma
Narcotics
Organic chemistry
Peptide Hydrolases - metabolism
Proteasomes
Proteins
Proteolysis - drug effects
Proteome - metabolism
Proteomes
Residues
Saturation mutagenesis
Structural analysis
Structure-function relationships
Substrates
Thalidomide
Thalidomide - analogs & derivatives
Thalidomide - pharmacology
Transcription factors
Ubiquitin
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
Ubiquitination - drug effects
Zinc
Zinc finger proteins
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cited_by cdi_FETCH-LOGICAL-c487t-1de7abb085dd1c39993bb1e2135457142d277e644d74577092be7219493305d73
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container_issue 6414
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container_title Science (American Association for the Advancement of Science)
container_volume 362
creator Sievers, Quinlan L
Petzold, Georg
Bunker, Richard D
Renneville, Aline
Słabicki, Mikołaj
Liddicoat, Brian J
Abdulrahman, Wassim
Mikkelsen, Tarjei
Ebert, Benjamin L
Thomä, Nicolas H
description The small molecules thalidomide, lenalidomide, and pomalidomide induce the ubiquitination and proteasomal degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) by recruiting a Cys -His (C2H2) zinc finger domain to Cereblon (CRBN), the substrate receptor of the CRL4 E3 ubiquitin ligase. We screened the human C2H2 zinc finger proteome for degradation in the presence of thalidomide analogs, identifying 11 zinc finger degrons. Structural and functional characterization of the C2H2 zinc finger degrons demonstrates how diverse zinc finger domains bind the permissive drug-CRBN interface. Computational zinc finger docking and biochemical analysis predict that more than 150 zinc fingers bind the drug-CRBN complex in vitro, and we show that selective zinc finger degradation can be achieved through compound modifications. Our results provide a rationale for therapeutically targeting transcription factors that were previously considered undruggable.
doi_str_mv 10.1126/science.aat0572
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We screened the human C2H2 zinc finger proteome for degradation in the presence of thalidomide analogs, identifying 11 zinc finger degrons. Structural and functional characterization of the C2H2 zinc finger degrons demonstrates how diverse zinc finger domains bind the permissive drug-CRBN interface. Computational zinc finger docking and biochemical analysis predict that more than 150 zinc fingers bind the drug-CRBN complex in vitro, and we show that selective zinc finger degradation can be achieved through compound modifications. Our results provide a rationale for therapeutically targeting transcription factors that were previously considered undruggable.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.aat0572</identifier><identifier>PMID: 30385546</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Adaptor Proteins, Signal Transducing ; Amino Acid Sequence ; Amino acids ; Analogs ; Binding ; Biochemical analysis ; Blood cancer ; Cancer ; Catalysis ; Computation ; Computer applications ; Conserved sequence ; Crystal structure ; CYS2-HIS2 Zinc Fingers ; Degradation ; Docking ; Domains ; Drug dependence ; Drug development ; Drugs ; Fingers ; Genomes ; HEK293 Cells ; Humans ; Ikaros protein ; Ikaros Transcription Factor - metabolism ; Lenalidomide - pharmacology ; Multiple myeloma ; Narcotics ; Organic chemistry ; Peptide Hydrolases - metabolism ; Proteasomes ; Proteins ; Proteolysis - drug effects ; Proteome - metabolism ; Proteomes ; Residues ; Saturation mutagenesis ; Structural analysis ; Structure-function relationships ; Substrates ; Thalidomide ; Thalidomide - analogs &amp; derivatives ; Thalidomide - pharmacology ; Transcription factors ; Ubiquitin ; Ubiquitin-protein ligase ; Ubiquitin-Protein Ligases - metabolism ; Ubiquitination ; Ubiquitination - drug effects ; Zinc ; Zinc finger proteins</subject><ispartof>Science (American Association for the Advancement of Science), 2018-11, Vol.362 (6414)</ispartof><rights>Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. 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We screened the human C2H2 zinc finger proteome for degradation in the presence of thalidomide analogs, identifying 11 zinc finger degrons. Structural and functional characterization of the C2H2 zinc finger degrons demonstrates how diverse zinc finger domains bind the permissive drug-CRBN interface. Computational zinc finger docking and biochemical analysis predict that more than 150 zinc fingers bind the drug-CRBN complex in vitro, and we show that selective zinc finger degradation can be achieved through compound modifications. 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subjects Adaptor Proteins, Signal Transducing
Amino Acid Sequence
Amino acids
Analogs
Binding
Biochemical analysis
Blood cancer
Cancer
Catalysis
Computation
Computer applications
Conserved sequence
Crystal structure
CYS2-HIS2 Zinc Fingers
Degradation
Docking
Domains
Drug dependence
Drug development
Drugs
Fingers
Genomes
HEK293 Cells
Humans
Ikaros protein
Ikaros Transcription Factor - metabolism
Lenalidomide - pharmacology
Multiple myeloma
Narcotics
Organic chemistry
Peptide Hydrolases - metabolism
Proteasomes
Proteins
Proteolysis - drug effects
Proteome - metabolism
Proteomes
Residues
Saturation mutagenesis
Structural analysis
Structure-function relationships
Substrates
Thalidomide
Thalidomide - analogs & derivatives
Thalidomide - pharmacology
Transcription factors
Ubiquitin
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
Ubiquitination - drug effects
Zinc
Zinc finger proteins
title Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN
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