Asset Details
Do you wish to reserve the book?
Structure of the human Cereblon–DDB1–lenalidomide complex reveals basis for responsiveness to thalidomide analogs
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
Structure of the human Cereblon–DDB1–lenalidomide complex reveals basis for responsiveness to thalidomide analogs
Do you wish to request the book?
Structure of the human Cereblon–DDB1–lenalidomide complex reveals basis for responsiveness to thalidomide analogs
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
Structure of the human Cereblon–DDB1–lenalidomide complex reveals basis for responsiveness to thalidomide analogs
2014
Overview
The protein Cereblon, part of an ubiquitin E3 ligase complex, is the target for anticancer thalidomide analogs. The crystal structure of human Cereblon-DDB1 with bound lenalidomide reveals how the drug affects E3 substrate recruitment.
The Cul4–Rbx1–DDB1–Cereblon E3 ubiquitin ligase complex is the target of thalidomide, lenalidomide and pomalidomide, therapeutically important drugs for multiple myeloma and other B-cell malignancies. These drugs directly bind Cereblon (CRBN) and promote the recruitment of substrates Ikaros (IKZF1) and Aiolos (IKZF3) to the E3 complex, thus leading to substrate ubiquitination and degradation. Here we present the crystal structure of human CRBN bound to DDB1 and the drug lenalidomide. A hydrophobic pocket in the thalidomide-binding domain (TBD) of CRBN accommodates the glutarimide moiety of lenalidomide, whereas the isoindolinone ring is exposed to solvent. We also solved the structures of the mouse TBD in the apo state and with thalidomide or pomalidomide. Site-directed mutagenesis in lentiviral-expression myeloma models showed that key drug-binding residues are critical for antiproliferative effects.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 82/80
/ 82/83
/ Angiogenesis Inhibitors - chemistry
/ Angiogenesis Inhibitors - pharmacology
/ Animals
/ Crystals
/ DNA-Binding Proteins - chemistry
/ DNA-Binding Proteins - metabolism
/ Humans
/ Mice
/ Molecular Docking Simulation
/ Peptide Hydrolases - chemistry
/ Peptide Hydrolases - metabolism
/ Proteins
/ Solvents
