Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide
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Author
Fischer, Eric S.
Böhm, Kerstin
Lydeard, John R.
Yang, Haidi
Stadler, Michael B.
Cavadini, Simone
Nagel, Jane
Serluca, Fabrizio
Acker, Vincent
Lingaraju, Gondichatnahalli M.
Tichkule, Ritesh B.
Schebesta, Michael
Forrester, William C.
Schirle, Markus
Hassiepen, Ulrich
Ottl, Johannes
Hild, Marc
Beckwith, Rohan E. J.
Harper, J. Wade
Jenkins, Jeremy L.
Thomä, Nicolas H.
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/nature13527Metadata
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Fischer, E. S., K. Böhm, J. R. Lydeard, H. Yang, M. B. Stadler, S. Cavadini, J. Nagel, et al. 2015. “Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide.” Nature 512 (7512): 49-53. doi:10.1038/nature13527. http://dx.doi.org/10.1038/nature13527.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 its teratogenicity, thalidomide and its derivatives lenalidomide and pomalidomide (together known as Immunomodulatory Drugs: IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-dysplasia. IMiDs target the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase and promote the ubiquitination of Ikaros/Aiolos transcription factors by CRL4CRBN. Here we present the crystal structure of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes CRBN as a CRL4CRBN substrate receptor, which enantioselectively binds IMiDs. Through an unbiased screen we identify the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4CRBN. Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4CRBN when recruiting Ikaros/Aiolos for degradation. This dual activity implies that small molecules can principally modulate a ligase to up- or down-regulate the ubiquitination of proteins.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423819/pdf/Terms of Use
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