Publication Date:
2016-02-26
Description:
Thalidomide and its derivatives, lenalidomide and pomalidomide, are immune modulatory drugs (IMiDs) used in the treatment of haematologic malignancies. IMiDs bind CRBN, the substrate receptor of the CUL4-RBX1-DDB1-CRBN (also known as CRL4(CRBN)) E3 ubiquitin ligase, and inhibit ubiquitination of endogenous CRL4(CRBN) substrates. Unexpectedly, IMiDs also repurpose the ligase to target new proteins for degradation. Lenalidomide induces degradation of the lymphoid transcription factors Ikaros and Aiolos (also known as IKZF1 and IKZF3), and casein kinase 1alpha (CK1alpha), which contributes to its clinical efficacy in the treatment of multiple myeloma and 5q-deletion associated myelodysplastic syndrome (del(5q) MDS), respectively. How lenalidomide alters the specificity of the ligase to degrade these proteins remains elusive. Here we present the 2.45 A crystal structure of DDB1-CRBN bound to lenalidomide and CK1alpha. CRBN and lenalidomide jointly provide the binding interface for a CK1alpha beta-hairpin-loop located in the kinase N-lobe. We show that CK1alpha binding to CRL4(CRBN) is strictly dependent on the presence of an IMiD. Binding of IKZF1 to CRBN similarly requires the compound and both, IKZF1 and CK1alpha, use a related binding mode. Our study provides a mechanistic explanation for the selective efficacy of lenalidomide in del(5q) MDS therapy. We anticipate that high-affinity protein-protein interactions induced by small molecules will provide opportunities for drug development, particularly for targeted protein degradation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Petzold, Georg -- Fischer, Eric S -- Thoma, Nicolas H -- England -- Nature. 2016 Apr 7;532(7597):127-30. doi: 10.1038/nature16979. Epub 2016 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. ; University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26909574" target="_blank"〉PubMed〈/a〉
Keywords:
Binding Sites/drug effects
;
Casein Kinase Ialpha/chemistry/*metabolism
;
Catalytic Domain
;
Crystallography, X-Ray
;
Humans
;
Ikaros Transcription Factor/chemistry/metabolism
;
Models, Molecular
;
Protein Binding/drug effects
;
Proteolysis/drug effects
;
Structure-Activity Relationship
;
Substrate Specificity/drug effects
;
Thalidomide/*analogs & derivatives/chemistry/metabolism/pharmacology
;
Ubiquitin-Protein Ligases/chemistry/*metabolism
;
Ubiquitination/drug effects
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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