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PDBsum entry 4ci2
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DNA binding protein/protein binding
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PDB id
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4ci2
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References listed in PDB file
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Key reference
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Title
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Structure of the ddb1-Crbn e3 ubiquitin ligase in complex with thalidomide.
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Authors
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E.S.Fischer,
K.Böhm,
J.R.Lydeard,
H.Yang,
M.B.Stadler,
S.Cavadini,
J.Nagel,
F.Serluca,
V.Acker,
G.M.Lingaraju,
R.B.Tichkule,
M.Schebesta,
W.C.Forrester,
M.Schirle,
U.Hassiepen,
J.Ottl,
M.Hild,
R.E.Beckwith,
J.W.Harper,
J.L.Jenkins,
N.H.Thomä.
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Ref.
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Nature, 2014,
512,
49-53.
[DOI no: ]
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PubMed id
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Abstract
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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.
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