PDB-8ou5: Cereblon isoform 4 in complex with novel Benzamide-Type Cereblon ...

ID or keywords:

Entry

Database: PDB / ID: 8ou5

Title

Cereblon isoform 4 in complex with novel Benzamide-Type Cereblon Binder 11b

Components

Cereblon isoform 4

Keywords

SIGNALING PROTEIN / Cereblon / PROTAC / E3 / molecular glue

Function / homology

CULT domain / CULT domain profile. / metal ion binding / Chem-W1X / Cereblon isoform 4

Function and homology information

Biological species

Magnetospirillum gryphiswaldense (magnetotactic)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2.3 Å

Authors

Heim, C. / Bischof, L. / Hartmann, M.D.

Funding support

Germany, 1items

Citation

Journal: J.Med.Chem. / Year: 2023
Title: Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs.
Authors: Steinebach, C. / Bricelj, A. / Murgai, A. / Sosic, I. / Bischof, L. / Ng, Y.L.D. / Heim, C. / Maiwald, S. / Proj, M. / Voget, R. / Feller, F. / Kosmrlj, J. / Sapozhnikova, V. / Schmidt, A. / ...

History

Deposition	Apr 21, 2023	Deposition site: PDBE / Processing site: PDBE
Revision 1.0	Nov 15, 2023	Provider: repository / Type: Initial release
Revision 1.1	Nov 22, 2023	Group: Database references / Category: citation / citation_author Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	8ou5.cif.gz	293.7 KB	Display	PDBx/mmCIF format
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Validation report

Summary document	8ou5_validation.pdf.gz	963.6 KB	Display	wwPDB validaton report
Full document	8ou5_full_validation.pdf.gz	975 KB	Display
Data in XML	8ou5_validation.xml.gz	12 KB	Display
Data in CIF	8ou5_validation.cif.gz	16.4 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/ou/8ou5 ftp://data.pdbj.org/pub/pdb/validation_reports/ou/8ou5	HTTPS FTP

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Related structure data

Related structure data	8ou3C 8ou4C 8ou6C 8ou7C 8ou9C 8ouaC C: citing same article (ref.)
Similar structure data	Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

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Links

PDB pages	PDBj / wwPDB / NCBI

Deposited unit

A: Cereblon isoform 4

B: Cereblon isoform 4

C: Cereblon isoform 4

hetero molecules

41.9 kDa, 3 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

Idetical with deposited unit
defined by author
Evidence: gel filtration

Unit cell

Length a, b, c (Å)	56.839, 59.572, 88.484
Angle α, β, γ (deg.)	90.000, 90.000, 90.000
Int Tables number	19
Space group name H-M	P2₁2₁2₁

Noncrystallographic symmetry (NCS)

NCS domain:

ID	Ens-ID	Details
1	1	A
2	1	A
3	2	A
4	2	A
5	3	A
6	3	A

NCS domain segments:

Beg auth comp-ID: SER / Beg label comp-ID: SER / Auth asym-ID: A / Label asym-ID: A

Dom-ID	Component-ID	Ens-ID	End auth comp-ID	End label comp-ID	Auth seq-ID	Label seq-ID
1	1	1	ALA	ALA	20 - 123	21 - 124
2	1	1	ALA	ALA	20 - 123	21 - 124
3	2	2	PRO	PRO	20 - 122	21 - 123
4	2	2	PRO	PRO	20 - 122	21 - 123
5	3	3	PRO	PRO	20 - 122	21 - 123
6	3	3	PRO	PRO	20 - 122	21 - 123

NCS ensembles :

ID	Details
1	Local NCS retraints between domains: 1 2
2	Local NCS retraints between domains: 3 4
3	Local NCS retraints between domains: 5 6

#1: Protein	Cereblon isoform 4 Mass: 13703.577 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Magnetospirillum gryphiswaldense (magnetotactic) Gene: MGR_0879 / Production host: Escherichia coli (E. coli) / References: UniProt: A4TVL0
#2: Chemical	ChemComp-ZN / ZINC ION Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#3: Chemical	ChemComp-W1X / 4-azanyl-~{N}-[(3~{S})-2,6-bis(oxidanylidene)piperidin-3-yl]-2-(trifluoromethyl)benzamide Mass: 315.248 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₁₃H₁₂F₃N₃O₃ / Feature type: SUBJECT OF INVESTIGATION
#4: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 24 / Source method: isolated from a natural source / Formula: H₂O
Has ligand of interest	Y

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Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal	Density Matthews: 1.82 Å³/Da / Density % sol: 32.49 %
Crystal grow	Temperature: 294 K / Method: vapor diffusion / Details: 0.5 M (NH4)H2PO4

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
Detector	Type: DECTRIS EIGER2 S 16M / Detector: PIXEL / Date: Jun 17, 2022
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 1 Å / Relative weight: 1
Reflection	Resolution: 2.3→49.42 Å / Num. obs: 13895 / % possible obs: 99.97 % / Redundancy: 12.9 % / CC_1/2: 0.997 / Net I/σ(I): 10.48
Reflection shell	Resolution: 2.3→2.382 Å / Num. unique obs: 2193 / CC_1/2: 0.58

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0405	refinement
XDS		data reduction
XDS		data scaling
REFMAC		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 2.3→49.416 Å / Cor.coef. F_o:F_c: 0.956 / Cor.coef. F_o:F_c free: 0.931 / SU B: 20.037 / SU ML: 0.208 / Cross valid method: THROUGHOUT / ESU R: 0.365 / ESU R Free: 0.248
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.2533	693	4.99 %
R_work	0.2045	13196	-
all	0.207	-	-
obs	-	13889	99.993 %

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT

Displacement parameters

B_iso mean: 57.484 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-0.099 Å²	0 Å²	0 Å²
2-	-	0.533 Å²	-0 Å²
3-	-	-	-0.434 Å²

Refinement step

Cycle: LAST / Resolution: 2.3→49.416 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	2221	0	47	24	2292

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.003	0.011	2357
X-RAY DIFFRACTION	r_bond_other_d	0.004	0.016	2048
X-RAY DIFFRACTION	r_angle_refined_deg	0.958	1.631	3205
X-RAY DIFFRACTION	r_angle_other_deg	0.373	1.57	4669
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	7.512	5	294
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	10.631	6.6	25
X-RAY DIFFRACTION	r_dihedral_angle_other_2_deg	0.034	10	2
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	12.488	10	304
X-RAY DIFFRACTION	r_dihedral_angle_6_deg	17.591	10	100
X-RAY DIFFRACTION	r_chiral_restr	0.047	0.2	318
X-RAY DIFFRACTION	r_gen_planes_refined	0.004	0.02	2854
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	638
X-RAY DIFFRACTION	r_nbd_refined	0.18	0.2	343
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.194	0.2	1721
X-RAY DIFFRACTION	r_nbtor_refined	0.184	0.2	1091
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.081	0.2	1197
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.108	0.2	62
X-RAY DIFFRACTION	r_metal_ion_refined	0.14	0.2	11
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.131	0.2	18
X-RAY DIFFRACTION	r_nbd_other	0.219	0.2	82
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.176	0.2	5
X-RAY DIFFRACTION	r_mcbond_it	1.387	3.732	1182
X-RAY DIFFRACTION	r_mcbond_other	1.386	3.733	1182
X-RAY DIFFRACTION	r_mcangle_it	2.317	6.703	1468
X-RAY DIFFRACTION	r_mcangle_other	2.316	6.704	1469
X-RAY DIFFRACTION	r_scbond_it	1.877	3.941	1175
X-RAY DIFFRACTION	r_scbond_other	1.876	3.942	1176
X-RAY DIFFRACTION	r_scangle_it	3.206	7.16	1735
X-RAY DIFFRACTION	r_scangle_other	3.205	7.16	1736
X-RAY DIFFRACTION	r_lrange_it	4.99	39.341	2515
X-RAY DIFFRACTION	r_lrange_other	4.989	39.342	2516
X-RAY DIFFRACTION	r_ncsr_local_group_1	0.077	0.05	3047
X-RAY DIFFRACTION	r_ncsr_local_group_2	0.106	0.05	2101
X-RAY DIFFRACTION	r_ncsr_local_group_3	0.11	0.05	2056

Refine LS restraints NCS

Ens-ID	Dom-ID	Auth asym-ID	Refine-ID	Type	Rms dev position (Å)	Weight position
1	1	A	X-RAY DIFFRACTION	Local ncs	0.0774	0.0501
1	2	A	X-RAY DIFFRACTION	Local ncs	0.0774	0.0501
2	3	A	X-RAY DIFFRACTION	Local ncs	0.10628	0.05009
2	4	A	X-RAY DIFFRACTION	Local ncs	0.10628	0.05009
3	5	A	X-RAY DIFFRACTION	Local ncs	0.11035	0.05009
3	6	A	X-RAY DIFFRACTION	Local ncs	0.11035	0.05009

LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	R_factor all	Num. reflection all	Fsc free	Fsc work	% reflection obs (%)	WR_factor R_work
2.3-2.36	0.422	47	0.317	957	0.322	1004	0.903	0.921	100	0.305
2.36-2.424	0.299	49	0.296	926	0.296	975	0.925	0.93	100	0.276
2.424-2.494	0.341	43	0.295	910	0.297	953	0.923	0.936	100	0.273
2.494-2.571	0.39	52	0.296	890	0.301	942	0.937	0.94	100	0.277
2.571-2.655	0.292	45	0.271	842	0.272	887	0.942	0.952	100	0.24
2.655-2.748	0.282	44	0.26	837	0.261	881	0.954	0.955	100	0.224
2.748-2.851	0.256	44	0.218	796	0.22	840	0.96	0.967	100	0.178
2.851-2.967	0.23	39	0.2	769	0.201	808	0.969	0.974	100	0.17
2.967-3.099	0.288	37	0.183	747	0.188	784	0.955	0.978	100	0.157
3.099-3.249	0.206	39	0.18	701	0.181	740	0.969	0.98	100	0.158
3.249-3.424	0.193	36	0.177	679	0.178	715	0.982	0.981	100	0.158
3.424-3.631	0.214	34	0.178	649	0.18	683	0.972	0.982	100	0.166
3.631-3.88	0.257	33	0.185	613	0.189	646	0.961	0.981	100	0.176
3.88-4.189	0.173	29	0.17	569	0.17	598	0.979	0.984	100	0.166
4.189-4.585	0.247	29	0.155	537	0.16	566	0.971	0.986	100	0.16
4.585-5.121	0.256	25	0.156	477	0.159	502	0.968	0.984	100	0.166
5.121-5.902	0.202	23	0.237	435	0.235	458	0.98	0.97	100	0.244
5.902-7.203	0.292	19	0.261	372	0.263	391	0.95	0.963	100	0.267
7.203-10.081	0.437	16	0.225	299	0.232	315	0.928	0.969	100	0.246
10.081-49.416	0.238	10	0.245	189	0.245	200	0.966	0.96	99.5	0.294

Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

ID	L11 (°²)	L12 (°²)	L13 (°²)	L22 (°²)	L23 (°²)	L33 (°²)	S11 (Å °)	S12 (Å °)	S13 (Å °)	S21 (Å °)	S22 (Å °)	S23 (Å °)	S31 (Å °)	S32 (Å °)	S33 (Å °)	T11 (Å²)	T12 (Å²)	T13 (Å²)	T22 (Å²)	T23 (Å²)	T33 (Å²)	Origin x (Å)	Origin y (Å)	Origin z (Å)
1	2.4437	-0.0423	0.9468	3.245	1.7315	5.4345	0.0136	0.0513	-0.3303	-0.1818	-0.0521	0.0449	0.0638	-0.0126	0.0386	0.1021	0.02	-0.0285	0.1741	-0.0229	0.0764	19.0971	17.9283	1.8286
2	4.5128	-1.089	0.7198	4.0831	-0.6999	2.6279	-0.0739	-0.0588	-0.0449	-0.0104	0.1092	0.042	-0.0274	0.085	-0.0352	0.1192	0.0019	0.0096	0.1331	0.0129	0.0028	31.9952	7.5005	24.0115
3	4.5416	1.9678	1.1202	3.9841	-0.1282	2.5907	0.094	-0.1649	-0.2234	-0.1007	0.0386	0.6847	0.2152	-0.659	-0.1325	0.4018	-0.0235	0.1106	0.5574	0.0575	0.4216	30.0653	-5.877	-6.8767

Refinement TLS group

Selection: ALL

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