title: Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide.
abstract: In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4(CRBN). Here we present crystal structures of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4(CRBN) and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4(CRBN). Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4(CRBN) while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins.
authors.affiliation: 1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland [2] University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Fischer
authors.affiliation: 1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland [2] University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Böhm
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Lydeard
authors.affiliation: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Haidi
authors.initials: H
authors.lastname: Yang
authors.affiliation: 1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland [2] University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland [3] Swiss Institute of Bioinformatics, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Stadler
authors.affiliation: 1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland [2] University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland.
authors.forename: Simone
authors.initials: S
authors.lastname: Cavadini
authors.affiliation: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Nagel
authors.affiliation: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Serluca
authors.affiliation: Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Acker
authors.affiliation: 1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland [2] University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland.
authors.forename: Gondichatnahalli M
authors.initials: GM
authors.lastname: Lingaraju
authors.affiliation: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Ritesh B
authors.initials: RB
authors.lastname: Tichkule
authors.affiliation: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Schebesta
authors.affiliation: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Forrester
authors.affiliation: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Schirle
authors.affiliation: Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hassiepen
authors.affiliation: Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Ottl
authors.affiliation: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Hild
authors.affiliation: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Rohan E J
authors.initials: RE
authors.lastname: Beckwith
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
authors.affiliation: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Jenkins
authors.affiliation: 1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland [2] University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland.
authors.forename: Nicolas H
authors.initials: NH
authors.lastname: Thomä
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D000077269:Lenalidomide; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D010447:Peptide Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013792:Thalidomide / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C491172:MEIS2 protein, human; D046912:Multiprotein Complexes; D014157:Transcription Factors; D013792:Thalidomide; C467566:pomalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D000077269:Lenalidomide