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The Structure of DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide

Fischer, Eric and Boehm, Kerstin and Lydeard, John R. and Lingaraju Gondichatnahalli, Manjappa and Cavadini, Simone and Acker, Vincent and Ottl, Johannes and Harper, Wade J. and Thomae, Nicolas and Stadler, Michael and Yang, Haidi and Nagel, Jane and Hassiepen, Ulrich and Hild, Marc and Forrester, William and Beckwith, Rohan and Schirle, Markus and Jenkins, Jeremy and Serluca-Aegerter, Fabrizio and Tichkule, Ritesh and Schebesta, Michael (2014) The Structure of DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature, 512 (7512). pp. 49-53. ISSN 0028-08361476-4687

Abstract

In the late 1950s the drug thalidomide (Contergan) was administered as a mild sedative to pregnant women leading to the birth of thousands of children with multiple birth defects including frequent limb deformities. Despite its teratogenicity, thalidomide and its derivatives have recently re-emerged as effective clinical drugs in treating multiple myeloma and 5q-dysplasias. The primary target of thalidomide is the CUL4(RBX1)-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase. We present the molecular architecture of the DDB1-CRBN complex bound to the small molecule inhibitors thalidomide, lenalidomide and pomalidomide. All compounds recognize a common binding site on CRBN. The CRL4CRBN architecture implicates CRBN in substrate binding and suggests that thalidomide and its derivatives can block substrate access to the receptor. Using an unbiased biochemical screen for CRL4CRBN substrates, we identify the homeobox transcription factor MEIS2 required for limb development as a CRL4CRBN ligase target, and show that its cellular levels are altered by thalidomide.

One Sentence Summary:
We present the molecular architecture of the CRL4CRBN ligase in complex with thalidomide and establish the homeobox transcription factor MEIS2 a substrate for the ligase.

Item Type: Article
Date Deposited: 18 May 2016 23:45
Last Modified: 04 Jul 2016 23:46
URI: https://oak.novartis.com/id/eprint/10741

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