Structural basis of lenalidomide-induced CK1α degradation by the CRL4(CRBN) ubiquitin ligase

Nature
Georg PetzoldNicolas H Thomä

Abstract

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 1α (CK1α), 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 Å crystal structure of DDB1-CRBN bound to lenalidomide and CK1α. CRBN and lenalidomide jointly provide the binding interface for a CK1α β-hairpin-loop located in the kinase N-lobe. We show that CK1α 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 CK1α, use a related binding mode. Our study prov...Continue Reading

References

Nov 1, 1995·Proteins·A SaliM Karplus
Nov 24, 1999·The New England Journal of Medicine·S SinghalB Barlogie
Apr 2, 2004·Nature Reviews. Cancer·J Blake BartlettAngus G Dalgleish
Feb 11, 2005·The New England Journal of Medicine·Alan ListJerome B Zeldis
Jul 14, 2005·European Journal of Drug Metabolism and Pharmacokinetics·Shufeng ZhouJames W Paxton
Nov 11, 2006·Proceedings of the National Academy of Sciences of the United States of America·Alexandr P KornevLynn F Ten Eyck
Aug 8, 2007·Journal of Molecular Biology·Evgeny Krissinel, Kim Henrick
Dec 9, 2008·Analytical Biochemistry·Wassim AbdulrahmanArnaud Poterszman
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Mar 13, 2010·Science·Takumi ItoHiroshi Handa
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
Aug 10, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Craig C HofmeisterMitch A Phelps
Apr 17, 2012·Acta Crystallographica. Section D, Biological Crystallography·Pavel V AfoninePaul D Adams
May 26, 2012·Science·P Andrew Karplus, Kay Diederichs
Jul 10, 2012·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Sandra RocheRobert O'Connor
Sep 10, 2013·Nature Immunology·Hilde SchjervenStephen T Smale
Apr 17, 2014·Chemical Reviews·Lech-Gustav MilroyChristian Ottmann
Jul 22, 2014·Nature·Eric S FischerNicolas H Thomä
Aug 12, 2014·Nature Structural & Molecular Biology·Philip P ChamberlainBrian E Cathers
Sep 23, 2014·Cancer Cell·Rebekka K SchneiderBenjamin L Ebert
Oct 15, 2014·Biomolecules·Cathal MahonElah Pick
Dec 3, 2014·Journal of Structural Biology·Marcus D HartmannBirte Hernandez Alvarez
Jun 9, 2015·Chemistry & Biology·Jing LuCraig M Crews

❮ Previous
Next ❯

Citations

Jun 25, 2016·Nature·Mary E MatyskielaPhilip P Chamberlain
Aug 6, 2016·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Stefanie Lindner, Jan Krönke
Sep 13, 2016·Expert Review of Hematology·Jonathan Canaani, Arnon Nagler
Mar 14, 2017·Nature Chemical Biology·Morgan S GaddAlessio Ciulli
Apr 14, 2017·Nature Chemical Biology·Michal J WalczakNicolas H Thomä
Apr 21, 2017·Journal of Medicinal Chemistry·Mary E MatyskielaPhilip P Chamberlain
Apr 25, 2017·Nature Chemical Biology·Taisuke UeharaTakashi Owa
Mar 14, 2017·Trends in Molecular Medicine·David Millrine, Tadamitsu Kishimoto
Jun 8, 2017·Structure·Teresa A F CardoteAlessio Ciulli
Apr 5, 2017·Annual Review of Biochemistry·Ning Zheng, Nitzan Shabek
Jun 22, 2017·Chemical Communications : Chem Comm·Caroline M RobbSandeep Rana
Jul 12, 2017·Expert Opinion on Drug Discovery·Sebastian A AndreiChristian Ottmann
Jul 27, 2017·Chemical Research in Toxicology·Tasaduq H WaniGoutam Chowdhury
Mar 17, 2018·Nature Reviews. Drug Discovery·Fleur M Ferguson, Nathanael S Gray
Feb 24, 2018·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Shanshan GuYongchao Zhao
May 2, 2018·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Sarah A HolsteinPhilip L McCarthy
Sep 27, 2018·ELife·Fernando Rodríguez-Pérez, Michael Rape
Oct 2, 2019·Future Medicinal Chemistry·Wenhai HuangZhengrong Shen
Sep 11, 2016·Clinical Science·Srila GopalIris Z Jaffe
Nov 2, 2019·Nature Reviews. Drug Discovery·Matthieu SchapiraCraig M Crews
Dec 11, 2019·Nature Chemical Biology·Dirksen E BussiereJoshiawa Paulk
Dec 11, 2019·Nature Chemical Biology·Kheewoong Baek, Brenda A Schulman
Aug 30, 2019·Oncogene·Xia LiuJiandong Chen
Aug 23, 2019·Medicinal Research Reviews·Catherine H Schein
Feb 19, 2020·Expert Review of Hematology·Elan GorsheinSteven Gore
Oct 9, 2019·Nature Chemical Biology·Tomoko Asatsuma-OkumuraHiroshi Handa

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.