4CI2

Structure of the DDB1-CRBN E3 ubiquitin ligase bound to lenalidomide

Summary for 4CI2

• Entry DOI: 10.2210/pdb4ci2/pdb
• Related: 2B5L 2B5M 3E0C 3EI1 3EI2 3EI3 3EI4 4A11 4CI1 4CI3
• Descriptor: DNA DAMAGE-BINDING PROTEIN 1, PROTEIN CEREBLON, ZINC ION, ... (5 entities in total)
• Functional Keywords: dna binding protein-protein binding complex, ubiquitin, cont, dna binding protein/protein binding
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 2
• Total formula weight: 183545.75

Authors

Fischer, E.S.,Boehm, K.,Thoma, N.H. (deposition date: 2013-12-05, release date: 2014-07-16, Last modification date: 2024-05-01)

Primary citation

Fischer, E.S.,Bohm, K.,Lydeard, J.R.,Yang, H.,Stadler, M.B.,Cavadini, S.,Nagel, J.,Serluca, F.,Acker, V.,Lingaraju, G.M.,Tichkule, R.B.,Schebesta, M.,Forrester, W.C.,Schirle, M.,Hassiepen, U.,Ottl, J.,Hild, M.,Beckwith, R.E.J.,Harper, J.W.,Jenkins, J.L.,Thoma, N.H.
Structure of the Ddb1-Crbn E3 Ubiquitin Ligase in Complex with Thalidomide.
Nature, 512:49-, 2014

PubMed 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.

PubMed: 25043012
DOI: 10.1038/NATURE13527

Experimental method

X-RAY DIFFRACTION (2.95 Å)