6UML

Structural Basis for Thalidomide Teratogenicity Revealed by the Cereblon-DDB1-SALL4-Pomalidomide Complex

Summary for 6UML

• Entry DOI: 10.2210/pdb6uml/pdb
• Descriptor: DNA damage-binding protein 1, Protein cereblon, Sal-like protein 4, ... (5 entities in total)
• Functional Keywords: celmod, cereblon-crl4, ubiquitin ligase, c2h2 zinc finger, ligase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 177358.87

Authors

Clayton, T.L.,Matyskiela, M.E.,Pagarigan, B.E.,Tran, E.T.,Chamberlain, P.P. (deposition date: 2019-10-09, release date: 2020-04-15, Last modification date: 2024-11-06)

Primary citation

Matyskiela, M.E.,Clayton, T.,Zheng, X.,Mayne, C.,Tran, E.,Carpenter, A.,Pagarigan, B.,McDonald, J.,Rolfe, M.,Hamann, L.G.,Lu, G.,Chamberlain, P.P.
Crystal structure of the SALL4-pomalidomide-cereblon-DDB1 complex.
Nat.Struct.Mol.Biol., 27:319-322, 2020

PubMed Abstract: Thalidomide-dependent degradation of the embryonic transcription factor SALL4 by the CRL4 E3 ubiquitin ligase is a plausible major driver of thalidomide teratogenicity. The structure of the second zinc finger of SALL4 in complex with pomalidomide, cereblon and DDB1 reveals the molecular details of recruitment. Sequence differences and a shifted binding position relative to Ikaros offer a path to the rational design of cereblon-binding drugs with reduced teratogenic risk.

PubMed: 32251415
DOI: 10.1038/s41594-020-0405-9

Experimental method

X-RAY DIFFRACTION (3.58 Å)