Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide

Eric S. Fischer, Kerstin Böhm, John R. Lydeard, Haidi Yang, Michael B. Stadler, Simone Cavadini, Jane Nagel, Fabrizio Serluca, Vincent Acker, Gondichatnahalli M. Lingaraju, Ritesh B. Tichkule, Michael Schebesta, William C. Forrester, Markus Schirle, Ulrich Hassiepen, Johannes Ottl, Marc Hild, Rohan E. J. Beckwith, J. Wade Harper, Jeremy L. Jenkins and Nicolas H. Thomä ()
Additional contact information
Eric S. Fischer: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland
Kerstin Böhm: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland
John R. Lydeard: Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA
Haidi Yang: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue
Michael B. Stadler: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland
Simone Cavadini: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland
Jane Nagel: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue
Fabrizio Serluca: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue
Vincent Acker: Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus, CH-4056 Basel, Switzerland
Gondichatnahalli M. Lingaraju: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland
Ritesh B. Tichkule: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue
Michael Schebesta: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue
William C. Forrester: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue
Markus Schirle: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue
Ulrich Hassiepen: Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus, CH-4056 Basel, Switzerland
Johannes Ottl: Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus, CH-4056 Basel, Switzerland
Marc Hild: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue
Rohan E. J. Beckwith: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue
J. Wade Harper: Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA
Jeremy L. Jenkins: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue
Nicolas H. Thomä: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland

Nature, 2014, vol. 512, issue 7512, 49-53

Abstract: 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 CRL4CRBN) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4CRBN. 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 CRL4CRBN and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4CRBN. Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4CRBN 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.

Date: 2014
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DOI: 10.1038/nature13527

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