Cereblon (CRBN) is the target of thalidomide derivatives1 that achieve therapeutic efficacy against some haematologic neoplasias2,3,4 by recruiting neosubstrates for degradation5,6,7. Despite the intense investigation of orthosteric thalidomide derivatives, little is known about alternate binding sites on CRBN. Here we report an evolutionarily conserved cryptic allosteric binding site on CRBN. Small-molecule SB-405483 binds the allosteric site to cooperatively enhance the binding of orthosteric ligands and alter their neosubstrate degradation profiles. A survey of over 100 orthosteric ligands and their degradation targets reveals trends in the classes of compounds and neosubstrates in which degradation outcomes are enhanced or inhibited by SB-405483. Structural investigations provide a mechanistic basis for the effects of the allosteric ligand by shifting the conformational distribution of CRBNopen to a novel CRBNint and increasing the CRBNclosed state. The discovery of a cryptic allosteric binding site on CRBN that alters the functional effects of orthosteric ligands opens new directions with broad implications for improving the selectivity and efficacy of CRBN therapeutics.
Dippon, V.N., Rizvi, Z., Choudhry, A.E. et al. Identification of an allosteric site on the E3 ligase adapter cereblon.
Nature (2026). https://doi.org/10.1038/s41586-025-09994-w
https://doi.org/10.1038/s41586-025-09994-w bu içeriği en az 2000 kelime olacak şekilde ve alt başlıklar ve madde içermiyecek şekilde ünlü bir science magazine için İngilizce olarak yeniden yaz. Teknik açıklamalar içersin ve viral olacak şekilde İngilizce yaz. Haber dışında başka bir şey içermesin. Haber içerisinde en az 12 paragraf ve her bir paragrafta da en az 50 kelime olsun. Cevapta sadece haber olsun. Ayrıca haberi yazdıktan sonra içerikten yararlanarak aşağıdaki başlıkların bilgisi var ise haberin altında doldur. Eğer bilgi yoksa ilgili kısmı yazma.:
Subject of Research:
Article Title:
Article References:
Dippon, V.N., Rizvi, Z., Choudhry, A.E. et al. Identification of an allosteric site on the E3 ligase adapter cereblon.
Nature (2026). https://doi.org/10.1038/s41586-025-09994-w
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41586-025-09994-w
Keywords
Tags: allosteric site identificationcereblon E3 ligase adaptercryptic allosteric binding sitesdrug selectivity and efficacy improvementsenhancing therapeutic efficacy in cancerimplications of allosteric modulation in drug discoveryneosubstrate degradation pathwaysnovel therapeutic targets in oncologyorthosteric ligands and allosteric interactionssmall-molecule ligands in drug designstructural biology of cereblonthalidomide derivatives mechanism
