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Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide
Abstract
In the 1950s the drug thalidomide administered as a sedative to pregnant women led to the birth of thousands of children with multiple defects. Despite its teratogenicity, thalidomide and its derivatives lenalidomide and pomalidomide (together known as Immunomodulatory Drugs: IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-dysplasia. IMiDs target the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase and promote the ubiquitination of Ikaros/Aiolos transcription factors by CRL4CRBN. Here we present the crystal structure of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes CRBN as a CRL4CRBN substrate receptor, which enantioselectively binds IMiDs. Through an unbiased screen we identify the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4CRBN. Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4CRBN when recruiting Ikaros/Aiolos for degradation. This dual activity implies that small molecules can principally modulate a ligase to up- or down-regulate the ubiquitination of proteins.
Thalidomide (α-(N-phthalimido)glutarimide) was introduced to the market in 1954 by Chemie Grünenthal. Initially promoted as a sedative with anti-emetic properties1,2, it became popular in the treatment of ‘morning sickness’3. In 1961, thalidomide taken in the first trimester of pregnancy was implicated in frequent limb deformities in infants4,5. Between 8,000 and 12,000 affected children were born before the drug was banned. Interest in thalidomide revived in 1965 when it was shown to have immunomodulatory and anti-inflammatory properties in erythema nodosum leprosum (ENL), an inflammatory complication of leprosy6. In 1994, thalidomide was found to inhibit fibroblast growth factor (bFGF)-induced formation of new blood vessels7. These findings prompted clinical trials exploring thalidomide use in anti-angiogenic cancer therapy. The efficacy of thalidomide and its derivatives lenalidomide and pomalidomide (collectively known as IMiDs) has since been demonstrated in several blood cancers8 : newly diagnosed multiple myeloma (thalidomide)9, refractory multiple myeloma (lenalidomide/pomalidomide) and 5q-deletion-associated myelodysplastic syndrome (lenalidomide).
The target of thalidomide, cereblon (CRBN), is a ubiquitously expressed protein that is part of the cullin-4 E3 ubiquitin ligase complex, CUL4-RBX1-DDB1 (CRL4)10. Mutations in CRBN are associated with autosomal recessive non-syndromic mental retardation (MR)11. In myeloma cells, the anti-proliferative activities of IMiDs are linked to CRBN expression12,13, making IMiDs the first clinically approved E3 ubiquitin ligase inhibitors with specificity for the CRL4CRBN ligase12. The IMiD anti-proliferative and immunomodulatory effects have recently been linked to drug-induced ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3) transcription factors by CRL4CRBN14 –16. Accordingly, loss of CRBN is a common determinant of drug resistance in myeloma cells12. How IMiD binding affects the CRL4CRBN ligase at the molecular level remains unclear. We set out to examine the role of CRBN within the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) E3-ligase complex, characterising the effect of IMiD binding on ligase activity.
Structure of DDB1-CRBN bound to IMiDs
We crystallized a chimeric complex of human DDB1 (DDB1) and chicken CRBN (ggCRBN) bound to thalidomide (refined to 3.0 Å), lenalidomide (3.0 Å) and pomalidomide (3.5 Å) (Fig. 1a, b and Extended Data Table 1). The high level of sequence conservation between human and chicken CRBN (Extended Data Fig. 1a, b) allows structural insights to be inferred directly from chicken to human CRBN. All subsequent biochemical and cell-biological experiments were performed with human full-length proteins. ggCRBN consists of three sub-domains (Extended Data Fig. 2a–f): a seven-stranded β-sheet located in the N-terminal domain (NTD, residues 1–185) (Extended Data Fig. 2a), a 7-α-helical bundle domain (HBD, residues 186–317) involved in DDB1 binding (Fig. 1c), and a C-terminal domain composed of 8 β-sheets (CTD, residues 318–445) (Fig. 1b). DDB1 comprises three seven-bladed WD40 β-propellers arranged in a triangular fashion (BPA, BPB and BPC)17 with ggCRBN attaching to a cavity between the BPA and BPC propellers (Fig. 1c). The molecular basis of the HBD-mediated attachment of ggCRBN to DDB1 defines a novel class of DDB1 binders and differs in detail from previous DDB1 attachment modules17 –20 (Extended Data Fig. 2e, f).
The ggCRBN N-terminal region (residues 46–317) including the NTD and HBD resembles the N-terminal domain of bacterial Lon proteases (PDB: 3LJC - RMSD of 2.7 Å over 178 residues aligned) (Extended Data Fig. 2b). The CTD harbours the thalidomide-binding pocket and contains a conserved Zn2+-binding site situated approximately 18 Å from the compound (Fig. 1a, b). The Zn2+ ion is coordinated through conserved cysteine residues 325, 328, 393 and 396. The ggCRBN-CTD shares structural similarity with the pseudouridine synthase and archaeosine transglycosylase (PUA) fold family21 involved in the binding of diverse sets of ligands (Extended Data Fig. 2c, d).
IMiD binding to CRBN
Thalidomide, lenalidomide and pomalidomide (Fig. 2a–c and Extended Data Fig. 3a–i) bind a pocket on the ggCRBN-CTD (Fig. 1b) situated in a surface groove that is highly conserved across CRBN orthologues (Extended Data Fig. 1b). The three ligands superimpose with very little deviation in the α-(isoindolinone-2-yl) glutarimide moiety, which contributes the majority of interactions between the receptor and the compounds and represents the main pharmacophore22. The glutarimide group is held in a buried cavity between ggCRBN sheets β10 and β13(Fig. 2d). Glutarimide carbonyls (C2, C6) and the intervening amide (N1) are in hydrogen-bonding distance to ggCRBN residues His380 and Trp382, respectively (Fig. 2c, d). A delocalised lone pair connects the glutarimide nitrogen with the two glutarimide carbonyls (C2-N1-C6) and is coplanar with Trp382. The opposing aliphatic face of the glutarimide ring (C3, C4 and C5) is in tight Van-der-Waals contact with a hydrophobic pocket lined by Trp382, Trp388, Trp402 and Phe404. In vitro, mutations of Tyr386 (affecting the integrity of the binding pocket) and Trp388 (directly involved in compound binding) to alanine ablate binding of all three IMiDs to CRBN (Extended Data Fig. 4a–c)10. Mutations of the equivalent residues render CRL4CRBN insensitive to the presence of thalidomide and lenalidomide in vivo10,12. In addition to near identical binding modes, we found that thalidomide, lenalidomide and pomalidomide have similar affinities for CRBN with dissociation constants of ~250 nM, ~178 nM and ~157 nM, respectively (Extended Data Fig. 4d–h).
Thalidomide and lenalidomide/pomalidomide differ in the C4 phthalimide aniline functionality (Fig. 2a–c), which is found in a solvent-exposed position. The common carbonyl at the phthaloyl C1-position contributes a water mediated hydrogen bond to His359, which anchors the phthaloyl ring-system together with stacking interactions provided by the aliphatic face of Pro354 (Fig. 2d). The phthalimide C5 and C6 positions are fully solvent exposed. The overall shape of the buried IMiD binding pocket, favours binding of (S)-thalidomide over the (R)-enantiomer (Fig. 2e), which is in agreement within vivo experiments12.
CRBN functions as a DCAF for the CRL4CRBN ligase
Within the CRL4 ligase family, DDB1 functions as the adaptor connecting the substrate receptor to the CUL4 ligase17,19,23. More than a dozen substrate receptors, including CRBN, have been identified (designated DCAFs: DDB1 CUL4 associated factor). ggCRBN, despite lacking the canonical DCAF WD40 fold, resembles a substrate receptor in dimensions and position on DDB1 (Extended Data Fig. 5a, b). The thalidomide binding site is situated where substrates generally bind to WD40 DCAFs (see e.g. DDB2-engaging DNA Fig. 3a and Extended Data Fig. 5a, b). Equivalent residues in the structurally related PUA domain-containing proteins are directly engaged in ligand binding (Extended Data Fig. 5c–e). The PUA domain of CRBN has striking structural similarity to a member of the methionine sulfoxide reductase (Extended Data Fig. 2c, d). In ggCRBN, the now defunct active centre of the reductase interacts with the IMiDs. Truncation of the CRBN C-terminus bordering the conserved thalidomide-binding pocket has been found in non-syndromic mental retardation (see Extended Data Fig. 6a–c for analysis of CRBN mutations).
Within CUL4-RBX1-DDB1-DCAF complexes, the cullin was found to freely rotate up to 150° around DDB1 (Fig. 3a, b)24,25. CUL4 mobility is undirected and driven exclusively by Brownian motion. Given the strictly modular architecture of the CRL4 family23,24,25, the structure of the CRL4CRBN ligase can be predicted with high confidence (Fig. 3b). Rotation of the CUL4 ligase arm around DDB1 and CRBN establishes a ubiquitination zone with dimensions of up to 340Å × 110Å × 30Å (Fig. 3b), with the centre of rotation near the thalidomide-binding site. The CRL4 ligase is promiscuous, targeting lysines that cross this ubiquitination zone. Accordingly, we observe in vitro that CRBN is autoubiquitinated (Extended Data Fig. 7a–d) at the unstructured N-terminal tail (residues K39 and K43, see also Extended Data Fig. 7d). We find that CRBN autoubiquitination persisted in the presence of IMiDs in vitro (Extended Data Fig. 7b) and is subject to inhibition by the Cop9 signalosome (CSN) (Extended Data Fig. 7b, c).
Pomalidomide and lenalidomide effectively target the Ikaros transcription factors IKFZ1 and 3 for degradation by CRL4CRBN. Thalidomide, on the other hand, is here less efficient14 –16 (Fig. 3c). All three IMiDs have comparable affinities for CRBN (Extended Data Fig. 4e–h) and similar predicted membrane permeabilities (Extended Data Fig. 7e). The major structural difference between CRBN-bound lenalidomide/pomalidomide and thalidomide lies in the presence of the solvent-exposed C4aniline functionality in the former. Therefore, different functional groups at the phthaloyl C4, C5 and C6 positions were tested for their ability to degrade Ikaros in a dual luciferase reporter assay14 (see Methods). Small groups attached to C4 (-NH3; -CH3 and to some extent -Cl) promote Ikaros degradation (Fig. 3c). On the other hand, larger substituents at the C4, or C5 and C6 positions were less effective in Ikaros degradation. These modifications are not expected to affect CRBN binding, as even a large substituent at the C4 position had no adverse effect on affinity (Extended Data Fig. 4d). Assuming comparable cellular concentrations27,28,29, this would imply that solvent-exposed bulky groups at C4 (and methyl groups at C5 and C6) interfere with Ikaros binding. The aniline and methyl substituents at C4, on the other hand, appear to contribute to Ikaros degradation, likely through direct interactions.
MEIS2 is an endogenous CRL4CRBN ligase substrate
Next, we set out to examine the effects of IMiDs on endogenous CRBN substrates, which have so far remained elusive. An unbiased biochemical screen was established to identify proteins ubiquitinated by CRL4CRBN. Human protein microarrays (~9,000 proteins) were used for on-chip ubiquitination by CRL4ACRBN in the presence of E1 (Uba1), E2 (UbcH5a), ubiquitin (biotin-ubiquitin) and ATP (Extended Data Fig. 8a–e). We reasoned that a substrate would be subject to ubiquitination by CRL4CRBN but not by a control ligase (CRL4Cdt2), that a substrate would overcome inhibition of the CRL4CRBN ligase by CSN24, and that ubiquitination of such substrates should be inhibited by lenalidomide. Following cluster analysis (43 clusters), we identified one cluster that best matched the expected ubiquitination profile (see Methods for details). In an orthogonal screen, the top five candidate genes (GRINL1A, MBOAT7, OTUD7B, C6orf141 and MEIS2) where overexpressed in HEK293T cells and assessed for lenalidomide induced changes insteady-state levels (Extended Data Fig. 8f). Of these, we focused on MEIS2, a transcription factor implicated in different aspects of human development30 –32, which we found was stabilised upon lenalidomide treatment (see below).
To recapitulate the on-chip results in solution, insect cell derived MEIS2 was used to establish a fully recombinant CRL4CRBN ubiquitination system. MEIS2 expressed from insect cells was isolated in a hyper-phosphorylated form. Dephosphorylation was found to improve protein behaviour, resulting in increasedMEIS2 ubiquitinationusing lysine-free (K0) ubiquitin (Fig. 4a compare lanes 1 and 2). MEIS2 ubiquitination was also observed using phosphorylated MEIS2 (data not shown). MEIS2 ubiquitination by CRL4CRBN was subject to inhibition by different IMiDs (Fig. 4a, lanes 4–8 and Extended Data Fig. 9a), irrespective of the chemical substituent at the C4, C5 and C6 positions. A CRL4CRBN mutant carrying the Y384A/W386A substitutions (CRBNYW/AA) that rendered the receptor unable to bind IMiDs (Extended Data Fig. 3a–c) also impaired MEIS2 ubiquitination (Extended Data Fig. 9b). In accordance with our on-chip results, we find that MEIS2 is able to relieve the inhibition of CRL4CRBN by CSN (Extended Data Fig. 9c) and is not ubiquitinated by the control ligases CRL4CSA and CRL4Cdt2 (Extended Data Fig. 9d). This data suggests that, within the CRL4CRBN complex, CRBN targets MEIS2 for ubiquitination in vitro with the aid of its IMiD binding site.
We next sought to test the effect of lenalidomide on MEIS2 half-life in cells by performing cycloheximide (CHX) chase experiments. RNA-seq. data from the cancer genome atlas (TCGA) identified the neuroblastoma cell line SK-N-DZ as having high levels of endogenous MEIS2 and CRBN transcripts. Following treatment with 100 µg/ml CHX, we found MEIS2 protein levels to be largely depleted after 3 h (Fig. 4b, lanes 1–4). Addition of 10 µM lenalidomide stabilised MEIS2 protein levels under these conditions (Fig. 4b, lanes 5–8). As SK-N-DZ cells were recalcitrant to transfection, we subsequently employed M059J cells, similarly characterized by high levels of MEIS2 mRNA (TCGA), to examine the effects of CRBN depletion by RNAi on MEIS2 abundance. For all experiments, endogenous MEIS2 levels were monitored by quantitative western blot using infrared detection (see Extended Data Fig. 9e–p). Four siRNAs were used to transfect M059J or HEK293T cells, resulting in efficient CRBN knockdown (Fig. 4c) and increased MEIS2 steady-state levels in M059J (Fig. 4c) and HEK293T (data not shown), implicating CRBN in MEIS2 turnover. To test whether lenalidomide treatment results in increased steady-state levels of MEIS2, M059J cells were treated with lenalidomide or a DMSO control. Following lenalidomide treatment endogenous MEIS2 was elevated up to 2.5-fold (Fig. 4d and Extended Data Fig. 9i–k). A similar level of steady-state MEIS2 stabilisation was observed with MLN4924 (Extended Data Fig. 9i, lane 6), a Nedd8-activating enzyme inhibitor, and with the proteasome inhibitor bortezomib (Extended Data Fig. 9i, lane 5). Increases in MEIS2 protein levels following lenalidomide exposure were not due to mRNA changes, as determined by quantitative RT-PCR (Extended Data Fig. 9m). When examining different IMiD derivatives, we found thalidomide, lenalidomide and pomalidomide to stabilise steady-state MEIS2 levels to a similar extent (Fig. 4d and Extended Data Fig. 9i, k). The effect of thalidomide on MEIS2 levels was also observed in vivo, where whole zebrafish embryos 24 h post-fertilisation showed a 1.5-fold increase in MEIS2 levels, comparable to that observed in cell lines (Extended Data Fig. 9l).
Thalidomide is an agonist and antagonist
We find in vitro and in vivo that IMiD binding is mutually exclusive with the recruitment of MEIS2 (Fig. 4a, 5a–c and Extended Data Fig. 9b). Accordingly, a stable cell line overexpressing an epitope-tagged MEIS2 together with a CRBNYW/AA mutant (Extended Data Fig. 9f, g) exhibited no changes in MEIS2 levels following addition of 40 µM lenalidomide. MEIS2 thus is an endogenous, IMiD-sensitive, target of CRBN (see Supplementary Discussion for a putative role of MEIS2 in IMiD mediated teratogenicity). Most CRL ligases studied so far target multiple substrates33,34. Given that IMiDs occupy the canonical ligand interface of the CRBN PUA domain, we also expect other endogenous substrates to be pre-empted from CRBN binding by thalidomide and its derivatives. On the other hand, IMiD-dependent targeting of Ikaros transcription factors (Fig. 5d) is facilitated by specific solvent-exposed functionalities that are not involved in CRBN binding. We propose a model where the interaction surface used for Ikaros binding comprises CRBN (in its IMiD-bound form) and the C4, C5 and C6 phthaloyl positions of the IMiD. While structural studies on CRBN-IMiD-Ikaros complexes are required to shed insights on the detailed binding mode, conceptually this mechanism bears striking similarities to auxin-induced degradation of Aux/IAA by the TIR1 ligase35 and to cyclosporine/FK506-induced cyclophilin/FKBP12 binding to calcineurin36,37. The CRL4 architecture supports ubiquitination in its vicinity, a property exploited by viral proteins in recruiting cellular targets for degradation by CRL4s17. As small molecules are apparently able to mimic this behaviour, it will be important to explore whether synthetic small molecules can promote the degradation of other substrates, which are not typically targeted by a specific ubiquitin ligase.
Our structure/function analysis indicates that IMiD-mediated Ikaros degradation interferes at the same time with the recruitment of endogenous substrates (such as MEIS2) to CRL4CRBN. Depending on the cell type and the proteins expressed, administration of thalidomide and its derivatives will thus simultaneously affect the levels of two groups of proteins: upregulating the endogenous substrates, while decreasing the neo-substrates. Thalidomide and its IMiD derivatives give rise to pleiotropic clinical manifestations ranging from anti-cancer and immunomodulatory properties to pronounced teratogenicity. Both loss of ubiquitination, as seen for MEIS2, as well as a gain of function seen for the Ikaros family and even complex synthetic combinations of these opposing changes need to be considered as underlying causes for these diverse clinical effects.
Extended Data
Extended Data Figure 1
Extended Data Figure 2
Extended Data Figure 3
Extended Data Figure 4
Extended Data Figure 5
Extended Data Figure 6
Extended Data Figure 7
Extended Data Figure 8
Extended Data Figure 9
Extended Data Table 1
hsDDB1-ggCRBN Thalidomide | hsDDB1-ggCRBN Lenalidomide | hsDDB1-ggCRBN Pomalidomide | |
---|---|---|---|
Data collection | P3221 | P3221 | P3221 |
Cell dimensions | |||
a, b, c (Å) | 172.2, 172.2, 140.1 | 172.1, 172.1, 139.8 | 172.1, 172.1, 137.9 |
α, β, γ (°) | 90, 90, 120 | 90, 90, 120 | 90, 90, 120 |
Resolution (Å) | 30.0-3.0 (3.1-3.0)* | 30.0-3.0 (3.2-3.0) | 30.0-3.5 (3.6-3.5) |
Rmerge (%) | 11.9 (137.4) | 11.1 (124.4) | 14.1 (131.7) |
I/σI | 15.77 (1.22) | 16.21 (1.66) | 7.05 (0.91) |
Completeness (%) | 100.0 (99.9) | 99.9 (99.9) | 84.4 (83.4) |
Redundancy | 7.9 (5.6) | 7.0 (7.0) | 7.0 (7.4) |
CC(1/2) | 0.99 (0.40) | 0.99 (0.53) | 0.99 (0.29) |
Refinement | |||
Resolution (Å) | 30.0-3.0 | 30.0-3.0 | 30.0-3.5 |
No. reflections | 49199 | 50542 | 25108 |
Rwork / Rfree | 19.7 / 23.3 | 19.3 / 23.4 | 21.2 / 23.5 |
No. atoms | |||
Protein | 11405 | 11411 | 11389 |
Ligand/ion | 20 | 20 | 21 |
Water | 35 | 8 | 0 |
B-factors | |||
Protein | 87.8 | 95.4 | 139.3 |
Ligand/ion | 67.2 | 54.3 | 93.5 |
Water | 56.3 | 60.5 | n.a. |
R.m.s deviations | |||
Bond lengths (Å) | 0.008 | 0.009 | 0.008 |
Bond angles (°) | 1.11 | 1.18 | 1.16 |
Acknowledgements
This work was supported by the Novartis Research Foundation and grants to N.H.T. from the European Research Council (ERC-2010-StG 260481-MoBa-CS), and to J.W.H. from the NIH (AG011085). J.R.L. was supported by a Damon Runyon Postdoctoral Fellowship DRG 2061-10. We acknowledge John Reilly (Novartis) for performing IAM experiments. We thank John Tallarico, Jeff Porter, William Sellers, Sylvain Cottens and Martin Renatus for help and comments. Daniel Hess, Ragna Sack and Jan Seebacher (FMI protein analysis facility) for the mass spectrometry analysis, and Jeremy Keusch and Heinz Gut (FMI protein structure facility) for support. We thank William Kaelin for kindly providing the IKZF1 reporter plasmid (pCMV-IRES-Renilla Luciferase-IRES-Gateway-Firefly Luciferase). Part of this work was performed at the Swiss Light Source, Paul Scherrer Institute, Villigen, Switzerland.
Footnotes
Supplementary information is linked to the online version of the paper at www.nature.com/nature.
Author Contributions E.S.F., N.H.T., J.L.J and W.C.F initiated the project. E.S.F. and K.B. conducted the protein purification and crystallisation. S.C. pre-screened protein complexes by EM. E.S.F collected data, processed and refined x-ray data. E.S.F. and N.H.T. analysed the structures. E.S.F. performed in vitro experiments and, with the help of U.H., developed and performed TR-FRET and FP assays. E.S.F. performed protein array experiments, M.B.S. and E.S.F. analysed the data. E.S.F., K.B., J.R.L., H.Y., M.H., J.W.H. and N.H.T. conceived and performed the cell biological characterisation. R.B.T. and R.E.J.B. conceived and conducted chemical syntheses. J.N. and M.S. performed proteomics. V.A. and J.O. did the DSF experiments. F.S. and M.S. did the zebrafish experiments. E.S.F. and N.H.T. wrote the manuscript. All authors assisted in editing the manuscript.
Author Information The following structural coordinates have been reported and were submitted to the Protein Data Bank under accession numbers: hsDDB1-ggCRBN-thalidomide (pdb:4CI1), hsDDB1-ggCRBN-lenalidomide (pdb:4CI2), hsDDB1-ggCRBN-pomalidomide (pdb:4CI3). Human protein microarray data sets generated for this study are available from GEO (http://www.ncbi.nlm.nih.gov/geo) under accession GSE57554.
Reprints and permissions information is available at www.nature.com/reprints.
The authors declare no competing financial interests.
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Funding
Funders who supported this work.
European Research Council (1)
Grant ID: 260481
NIA NIH HHS (2)
Grant ID: R01 AG011085
Grant ID: AG011085