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Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes


Heterobifunctional chimeric degraders are a class of ligands that recruit target proteins to E3 ubiquitin ligases to drive compound-dependent protein degradation. Advancing from initial chemical tools, protein degraders represent a mechanism of growing interest in drug discovery. Critical to the mechanism of action is the formation of a ternary complex between the target, degrader and E3 ligase to promote ubiquitination and subsequent degradation. However, limited insights into ternary complex structures exist, including a near absence of studies on one of the most widely co-opted E3s, cellular inhibitor of apoptosis 1 (cIAP1). In this work, we use a combination of biochemical, biophysical and structural studies to characterize degrader-mediated ternary complexes of Bruton’s tyrosine kinase and cIAP1. Our results reveal new insights from unique ternary complex structures and show that increased ternary complex stability or rigidity need not always correlate with increased degradation efficiency.

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Fig. 1: IAP degrades BTK via BC5P.
Fig. 2: The IAP–BTK–BC5P ternary complex is non-cooperative.
Fig. 3: The IAP–BTK–BC5P ternary complex is flexible.
Fig. 4: Structure-based linker design yields a degrader with distinct biochemical properties.
Fig. 5: Distinct IAP–BTK crystal structure.
Fig. 6: IAP–BTK can form higher-order assemblies.

Data availability

Structural coordinates from X-ray crystallography experiments have been deposited at RCSB with the following accession codes: 6W74 (cIAP1–BC5P binary structure), 6W7O (BTK–BCPyr–cIAP1 ternary structure) and 6W8I (BTK–BC5P–cIAP1 ternary structure). NMR data have been deposited to the Biological Magnetic Resonance Data Bank. Source data are provided with this paper.


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We thank K. Fennell and P. Montanaro for expression of [15N13C]cIAP1Bir3 used in the pilot NMR experiments, J. Chang for the protein purification schemes of cIAP1Bir3 and biotinylated BTKKD and L. Byrnes and A. Varghese for SEC MALS troubleshooting and analysis. We also thank J. Knafels for crystal preparation before synchrotron shipment and J. Smith for the THP-1 cell culture and degradation protocols. BC5P synthesis was assisted by A. Davies. Compounds BC2P and BCPyr were synthesized by Wuxi PharmaTech. We also thank K. Farley, A. Ratnayake and T. Ryder for assistance with small-molecule NMR analysis. All individuals named are current or former members of Pfizer Worldwide Research and Development, Groton CT, USA.

Author information




R.H. performed all protein NMR experiments and analyses. Y.M. performed computational modeling and analysis with guidance from Y.C. J.I.M. designed BCPyr and BCPip. X.F. performed native ESI MS and subsequent analysis. S.B. and D.P.U. performed compound synthesis. C.L., Y.X., M.F.B., M.M.H., A.M.G. and M.C.N. contributed to the interpretation of experimental data. J.S. and M.F.C. conceptualized the experimental work and contributed to data interpretation, manuscript drafting and revision. J.S. and M.F.C. performed crystal structure refinement. J.S. performed BLI experiments and analysis with guidance from K.B. J.S. performed cellular degradation assays, in vitro ubiquitination, protein expression and purification, crystallization, SEC MALS and cross-linking studies.

Corresponding author

Correspondence to Matthew F. Calabrese.

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All authors are current or former employees of Pfizer, Inc.

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Extended data

Extended Data Fig. 1 The BC2P Linker is Non-Permissive.

a, Two representative replicate experiments (top and bottom) of dose dependent BTK degradation in THP1 cells and associated DC50 curve-fit. b, Schematic representation of 2-PEG ‘BC2P’ (2), with regions corresponding to BTK ligand (magenta), linker (black) and cIAP1 ligand (blue) indicated. c, Western blot analysis of dose dependent BTK degradation in THP1 cells by BC5P (left), BC2P (right) and associated DC50 curve-fit. The experiment was repeated for a total of 3 independent experiments with reproducible findings (d) Rescue of BC5P dependent degradation using a BTK ligand, and corresponding vinculin loading control with densiometric quantification shown on the left. The experiment was repeated for a total of 5 independent experiments with reproducible findings. Filled circles and hollow triangles represent untreated or BTK ligand treated samples, respectively. Error bars represent ± 1 standard deviation and these data are a result of n=5 independent experiments. Statistical analysis was performed using a two-sided student’s unpaired T Test where significance (*) a p value of 0.022 and 0.033 for 2.5 μM and 0.083 μM treatments, respectively.

Extended Data Fig. 2 Anisotropic vs Isotropic Resolution of BC5P.

Electron density difference map examining ternary complex Pose 2, with BC5P. Anisotropic data (left), and isotropic data (right) with 2Fo-Fc σ = 1.0.

Extended Data Fig. 3 NMR Analysis and Backbone Assignments.

a, Overlay of [15N,1H]-COSY spectra with15N13C cIAP1Bir3 as either apo (red) or an IAP-ligand binary complex (blue). b, [15N,1H]-HSQC spectrum of uniformly 15N,13C-enriched cIAP1Bir3 in complex with the IAP-ligand. Backbone resonance assignments are indicated by the one-letter amino acid code and the sequence number. The backbone cross-peaks of G46 and C62 are outside of the region shown. c, TRO-STE spectra of cIAP1Bir3/BC5P/BTKKD. The relative signal intensity ln(S/So) is plotted versus the square of the field gradient strength, \(G_D^2\). Green triangles and black squares represent data for the apo form of cIAP1Bir3 and for the cIAP1Bir3/BC5P/BTKKD ternary complex, respectively. Translational diffusion coefficients, Dt, as calculated from the diffusion data are indicated.

Extended Data Fig. 4 BC5P Binary Crystal Structure.

a, Electron density difference map examining the binary crystal structure of cIAP1Bir3 and BC5P. Density substantially weakens over the benzyl portion of the tetrahydroisoquinoline, thus preventing further modeling of the linker. Protein is omitted on the right panel for clarity. b, Protein-Ligand interactions between BC5P and cIAP1Bir3 in the binary crystal structure. Dashed lines indicate a set of polar interactions ≤ 3.5 Å in length.

Extended Data Fig. 5 Ternary Complex Kinetics between cIAP1Bir3 and BTKKD.

a, Western blot image of in vitro ubiquitination of BTKKD by cIAP1BUCR1 in the presence of BC5P, or BCPyr. Quantification of mUb and pUb signal was done using ImageJ analysis (v1.4.3.67). b, Ternary complex assay sensorgram of a binary [cIAP1Bir3-BC5P] complex binding to BTKKD, and (c) [cIAP1Bir3-BCPyr] complex binding to BTKKD. For panel B, data was fit globally (left) or independently for Kon and Koff (right) yielding consistent affinity values.

Extended Data Fig. 6 Asymmetric Unit Analysis.

Electron density for the BTKKD/BCPyr/cIAP1Bir3 ternary complex structure covering a portion of the protein-protein interface (proximal to BTKKD R487). Left and middle panels show map (2Fo-Fc contoured at σ = 1.0) for the two copies in the asymmetric unit. Panel on the right shows an overlay of the two copies with density omitted. R487 sidechain is modeled in different conformations in the two copies, projecting toward either one or both aspartic acids presented by cIAP1.

Extended Data Fig. 7 BCPip Design and Characteristics.

a, Top panel: Crystallographic pose of BTKKD (gray), cIAP1Bir3 (orange), and BCPyr (light orange). Bottom panel: Linker substitution modeled to generate Piperidine ‘BCPip’ (4) (purple). b, Schematic representation of BCPip, with regions corresponding to BTK ligand (Magenta), linker (Black) and IAP ligand (Blue) indicated. c, Ternary complex assay sensorgram of a binary [cIAP1BUCR1-BCPip] complex binding to BTKKD. d, Western blot analysis of dose dependent BTK degradation in THP1 cells by BCPip and associated DC50 curve-fit.

Extended Data Fig. 8 Native ESI and SEC MALS Analysis.

a, Native ESI Mass spectrometry showing the spectrum for monomeric cIAP1BUCR1 (Top Panel) or a spectrum for cIAP1BUCR1/ BC5P (Bottom Panel). A Distinct M/Z shift between cIAP1BUCR1 monomer (+) and cIAP1BUCR1 monomer after BC5P (‡) treatment is indicative of a single molecule of BC5P binding to the monomer. The dimer fraction (#) is comprised of 2 molecules of BC5P bound to 2 molecules of cIAP1BUCR1. These data demonstrate a 1:1 or 2:2 stoichiometry of BC5P for cIAP1BUCR1. b, Size Exclusion Chromatography Multi-Angle Light Scattering (SEC MALS) chromatograph of a cIAP1BUCR1/BC5P dimer (red), a lower concentration intermediate (blue), and a DMSO treated cIAP1BUCR1 monomer (black). Calculated molecular weights are shown as squares, change in refractive index (dRI) is shown as dotted lines, light scattering (LS) is shown as solid lines, and expected molecular weights are shown as dashed light blue lines. c, SEC MALS chromatograph of a cIAP1BUCR1/BCPyr dimer (red), and a cIAP1BUCR1/BCPyr/BTKKD dimer of ternary complexes (purple). Calculated molecular weights shown as squares, change in refractive index (dRI) is shown as dotted lines, light scattering (LS) is shown as solid lines, and expected molecular weights are shown as dashed light blue lines. This experiment was performed 3 times with reproducible results.

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Schiemer, J., Horst, R., Meng, Y. et al. Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes. Nat Chem Biol 17, 152–160 (2021).

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