PDB-8ou4: Cereblon isoform 4 in complex with novel Benzamide-Type Cereblon ...

ID or keywords:

Entry

Database: PDB / ID: 8ou4

Title

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

Components

Cereblon isoform 4

Keywords

SIGNALING PROTEIN /

Cereblon /

PROTAC / E3 /

molecular glue

Function / homology

CULT domain / CULT domain profile. /

metal ion binding / Chem-W2F / Cereblon isoform 4

Function and homology information

Biological species

Magnetospirillum gryphiswaldense (magnetotactic)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2.25 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	8ou4.cif.gz	286.3 KB	Display	PDBx/mmCIF format
PDB format	pdb8ou4.ent.gz	176.9 KB	Display	PDB format
PDBx/mmJSON format	8ou4.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/ou/8ou4 ftp://data.pdbj.org/pub/pdb/validation_reports/ou/8ou4	HTTPS FTP

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Related structure data

Related structure data	8ou3C 8ou5C 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

A: Cereblon isoform 4

hetero molecules

defined by author
Evidence: gel filtration
14.1 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

2

B: Cereblon isoform 4

hetero molecules

defined by author
14.1 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

3

C: Cereblon isoform 4

hetero molecules

defined by author
13.8 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

Unit cell

Length a, b, c (Å)	56.511, 59.542, 88.185
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:

Auth asym-ID: A / Label asym-ID: A

Dom-ID	Component-ID	Ens-ID	Beg auth comp-ID	Beg label comp-ID	End auth comp-ID	End label comp-ID	Auth seq-ID	Label seq-ID
1	1	1	SER	SER	PRO	PRO	20 - 122	21 - 123
2	1	1	SER	SER	PRO	PRO	20 - 122	21 - 123
3	2	2	ALA	ALA	ALA	ALA	19 - 123	20 - 124
4	2	2	ALA	ALA	ALA	ALA	19 - 123	20 - 124
5	3	3	SER	SER	ALA	ALA	20 - 123	21 - 124
6	3	3	SER	SER	ALA	ALA	20 - 123	21 - 124

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-W2F / 4-azanyl-~{N}-[(3~{S})-2,6-bis(oxidanylidene)piperidin-3-yl]-2-chloranyl-benzamide Mass: 281.695 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₁₂H₁₂ClN₃O₃ / Feature type: SUBJECT OF INVESTIGATION
#4: Water	ChemComp-HOH / water / Water Mass: 18.015 Da / Num. of mol.: 18 / 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: 1.8 Å³/Da / Density % sol: 31.83 %
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: 2.25→47.58 Å / Num. obs: 14648 / % possible obs: 99.84 % / Redundancy: 12.9 % / CC_1/2: 0.998 / Net I/σ(I): 10.68
Reflection shell	Resolution: 2.25→2.331 Å / Num. unique obs: 2311 / CC_1/2: 0.631

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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: 2.25→47.58 Å / Cor.coef. F_o:F_c: 0.943 / Cor.coef. F_o:F_c free: 0.914 / SU B: 19.827 / SU ML: 0.213 / Cross valid method: THROUGHOUT / ESU R: 0.347 / ESU R Free: 0.248
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.2685	731	4.991 %
R_work	0.2218	13915	-
all	0.224	-	-
obs	-	14646	99.857 %

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: 53.339 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-0.241 Å²	-0 Å²	0 Å²
2-	-	0.147 Å²	-0 Å²
3-	-	-	0.094 Å²

Refinement step

Cycle: LAST / Resolution: 2.25→47.58 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	2185	0	41	18	2244

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.002	0.011	2323
X-RAY DIFFRACTION	r_bond_other_d	0.004	0.016	1979
X-RAY DIFFRACTION	r_angle_refined_deg	0.758	1.636	3166
X-RAY DIFFRACTION	r_angle_other_deg	0.309	1.57	4519
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	6.003	5	300
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	6.687	7.105	19
X-RAY DIFFRACTION	r_dihedral_angle_other_2_deg	0.028	10	2
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	10.903	10	259
X-RAY DIFFRACTION	r_dihedral_angle_6_deg	16.06	10	90
X-RAY DIFFRACTION	r_chiral_restr	0.038	0.2	320
X-RAY DIFFRACTION	r_gen_planes_refined	0.003	0.02	2796
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	596
X-RAY DIFFRACTION	r_nbd_refined	0.159	0.2	355
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.192	0.2	1672
X-RAY DIFFRACTION	r_nbtor_refined	0.179	0.2	1082
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.082	0.2	1158
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.12	0.2	60
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_other	0.01	0.2	1
X-RAY DIFFRACTION	r_metal_ion_refined	0.175	0.2	11
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.146	0.2	25
X-RAY DIFFRACTION	r_nbd_other	0.221	0.2	81
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.165	0.2	10
X-RAY DIFFRACTION	r_mcbond_it	1.068	4.288	1197
X-RAY DIFFRACTION	r_mcbond_other	1.068	4.288	1197
X-RAY DIFFRACTION	r_mcangle_it	1.826	7.694	1486
X-RAY DIFFRACTION	r_mcangle_other	1.826	7.695	1487
X-RAY DIFFRACTION	r_scbond_it	1.379	4.345	1126
X-RAY DIFFRACTION	r_scbond_other	1.379	4.346	1127
X-RAY DIFFRACTION	r_scangle_it	2.297	7.961	1676
X-RAY DIFFRACTION	r_scangle_other	2.296	7.961	1677
X-RAY DIFFRACTION	r_lrange_it	3.768	47.293	2485
X-RAY DIFFRACTION	r_lrange_other	3.767	47.293	2486
X-RAY DIFFRACTION	r_ncsr_local_group_1	0.078	0.05	3050
X-RAY DIFFRACTION	r_ncsr_local_group_2	0.067	0.05	2108
X-RAY DIFFRACTION	r_ncsr_local_group_3	0.074	0.05	2130

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	0.0781	0.05011
1	2	A	X-RAY DIFFRACTION	Local ncs	0.0781	0.05011
2	3	A	X-RAY DIFFRACTION	Local ncs	0.06731	0.0501
2	4	A	X-RAY DIFFRACTION	Local ncs	0.06731	0.0501
3	5	A	X-RAY DIFFRACTION	Local ncs	0.07448	0.05009
3	6	A	X-RAY DIFFRACTION	Local ncs	0.07448	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
2.25-2.309	0.396	49	0.336	996	0.339	1052	0.873	0.91	99.3346	0.335
2.309-2.372	0.301	53	0.287	996	0.288	1049	0.929	0.934	100	0.279
2.372-2.44	0.27	51	0.267	943	0.268	997	0.95	0.948	99.6991	0.251
2.44-2.515	0.319	49	0.269	928	0.272	980	0.926	0.948	99.6939	0.255
2.515-2.597	0.285	47	0.281	917	0.281	966	0.943	0.944	99.793	0.251
2.597-2.688	0.258	46	0.247	872	0.248	918	0.957	0.958	100	0.219
2.688-2.789	0.269	44	0.228	825	0.23	871	0.953	0.963	99.7704	0.2
2.789-2.903	0.314	43	0.219	816	0.224	860	0.947	0.968	99.8837	0.196
2.903-3.031	0.275	42	0.217	790	0.219	833	0.951	0.969	99.88	0.19
3.031-3.179	0.261	40	0.206	759	0.209	799	0.956	0.973	100	0.189
3.179-3.35	0.258	39	0.207	713	0.21	752	0.96	0.972	100	0.19
3.35-3.552	0.225	34	0.19	689	0.192	723	0.966	0.976	100	0.178
3.552-3.796	0.256	36	0.2	636	0.203	672	0.961	0.975	100	0.191
3.796-4.098	0.189	30	0.177	603	0.178	633	0.975	0.98	100	0.18
4.098-4.485	0.249	29	0.176	550	0.179	580	0.964	0.98	99.8276	0.182
4.485-5.009	0.282	26	0.176	521	0.18	547	0.956	0.979	100	0.191
5.009-5.774	0.226	25	0.256	452	0.255	477	0.974	0.963	100	0.276
5.774-7.045	0.357	20	0.292	393	0.295	413	0.923	0.953	100	0.306
7.045-9.856	0.316	17	0.232	318	0.235	335	0.938	0.964	100	0.264
9.856-47.58	0.303	11	0.283	198	0.284	209	0.935	0.943	100	0.331

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	3.167	0.1366	1.6193	2.8823	1.581	5.4579	0.0735	0.1313	-0.2979	-0.1575	-0.0267	0.1048	0.2073	0.0773	-0.0468	0.0339	0.0188	-0.0149	0.033	-0.0166	0.0431	18.9946	17.8382	1.8735
2	4.4883	-0.6716	0.315	3.8461	-0.9818	2.5151	-0.0321	-0.0118	0.0273	0.0454	0.0484	0.0004	0.0007	0.0876	-0.0163	0.0247	-0.0053	0.0027	0.0147	0.0033	0.0037	31.8221	7.643	23.8906
3	3.4311	1.6769	2.024	4.1287	-0.1857	4.5312	0.0419	-0.1186	-0.2556	-0.0604	0.0121	0.5815	0.3417	-0.684	-0.054	0.2601	-0.0627	0.0808	0.3739	0.0131	0.3426	29.7768	-6.1287	-7.3215

Refinement TLS group

Selection: ALL

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