6R0S

Cereblon isoform 4 from Magnetospirillum gryphiswaldense in complex with compound 4a and hydrolysis product

PDB DOI: https://doi.org/10.2210/pdb6R0S/pdb

Classification: SIGNALING PROTEIN
Organism(s): Magnetospirillum gryphiswaldense MSR-1
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2019-03-13 Released: 2019-08-07
Deposition Author(s): Heim, C., Hartmann, M.D.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.55 Å
R-Value Free: 0.213
R-Value Work: 0.187
R-Value Observed: 0.188

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

De-Novo Design of Cereblon (CRBN) Effectors Guided by Natural Hydrolysis Products of Thalidomide Derivatives.

Heim, C., Pliatsika, D., Mousavizadeh, F., Bar, K., Hernandez Alvarez, B., Giannis, A., Hartmann, M.D.

(2019) J Med Chem 62: 6615-6629

PubMed: 31251063 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acs.jmedchem.9b00454
Primary Citation of Related Structures:
6R0Q, 6R0S, 6R0U, 6R0V, 6R11, 6R12, 6R13, 6R18, 6R19, 6R1A, 6R1C, 6R1D, 6R1K, 6R1W, 6R1X

PubMed Abstract:
Targeted protein degradation via cereblon (CRBN), a substrate receptor of an E3 ubiquitin ligase complex, is an increasingly important strategy in various clinical settings, in which the substrate specificity of CRBN is altered via the binding of small-molecule effectors. To date, such effectors are derived from thalidomide and confer a broad substrate spectrum that is far from being fully characterized. Here, we employed a rational and modular approach to design novel and minimalistic CRBN effectors. In this approach, we took advantage of the binding modes of hydrolyzed metabolites of several thalidomide-derived effectors, which we elucidated via crystallography. These yielded key insights for the optimization of the minimal core binding moiety and its linkage to a chemical moiety that imparts substrate specificity. Based on this scaffold, we present a first active de-novo CRBN effector that is able to degrade the neo-substrate IKZF3 in the cell culture.

Organizational Affiliation

Department of Protein Evolution , Max Planck Institute for Developmental Biology , Max-Planck-Ring 5 , 72076 Tübingen , Germany.

Macromolecule Content

Total Structure Weight: 42.66 kDa
Atom Count: 2,871
Modelled Residue Count: 324
Deposited Residue Count: 378
Unique protein chains: 2

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Cereblon isoform 4	A, B, C	125	Magnetospirillum gryphiswaldense MSR-1	Mutation(s): 0 Gene Names: MGR_0879
UniProt
Find proteins for A4TVL0 (Magnetospirillum gryphiswaldense) Explore A4TVL0 Go to UniProtKB: A4TVL0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	A4TVL0
Sequence Annotations Expand
Reference Sequence

Find similar proteins by: Sequence | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
CEREBLON ISOFORM 4	D [auth F]	3	Magnetospirillum gryphiswaldense MSR-1	Mutation(s): 0
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 6 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
JOE Query on JOE Download Ideal Coordinates CCD File SDF format, chain I [auth B] MOL2 format, chain I [auth B] mmCIF format, chain I [auth B]	I [auth B]	2-[[(3~{S})-2,5-bis(oxidanylidene)pyrrolidin-3-yl]carbamoyl]-6-nitro-benzoic acid C₁₂ H₉ N₃ O₇ DWGKCZUFQWKKEW-LURJTMIESA-N		Interactions Focus chain I [auth B] Interactions & Density Focus chain I [auth B]
JOH Query on JOH Download Ideal Coordinates CCD File SDF format, chain M [auth C] MOL2 format, chain M [auth C] mmCIF format, chain M [auth C]	M [auth C]	2-[(3~{S})-2,5-bis(oxidanylidene)pyrrolidin-3-yl]-4-nitro-isoindole-1,3-dione C₁₂ H₇ N₃ O₆ NSOHSQDNWATGPD-ZETCQYMHSA-N		Interactions Focus chain M [auth C] Interactions & Density Focus chain M [auth C]
EF2 Query on EF2 Download Ideal Coordinates CCD File SDF format, chain F [auth A] MOL2 format, chain F [auth A] mmCIF format, chain F [auth A]	F [auth A]	S-Thalidomide C₁₃ H₁₀ N₂ O₄ UEJJHQNACJXSKW-VIFPVBQESA-N		Interactions Focus chain F [auth A] Interactions & Density Focus chain F [auth A]
PO4 Query on PO4 Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain J [auth B] MOL2 format, chain G [auth A] MOL2 format, chain J [auth B] mmCIF format, chain G [auth A] mmCIF format, chain J [auth B]	G [auth A], J [auth B]	PHOSPHATE ION O₄ P NBIIXXVUZAFLBC-UHFFFAOYSA-K		Interactions Focus chain G [auth A] Focus chain J [auth B] Interactions & Density Focus chain G [auth A] Focus chain J [auth B]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain H [auth B] SDF format, chain L [auth C] MOL2 format, chain E [auth A] MOL2 format, chain H [auth B] MOL2 format, chain L [auth C] mmCIF format, chain E [auth A] mmCIF format, chain H [auth B] mmCIF format, chain L [auth C]	E [auth A], H [auth B], L [auth C]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain H [auth B] Focus chain L [auth C] Interactions & Density Focus chain E [auth A] Focus chain H [auth B] Focus chain L [auth C]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain K [auth B] MOL2 format, chain K [auth B] mmCIF format, chain K [auth B]	K [auth B]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain K [auth B] Interactions & Density Focus chain K [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
EF2	BindingDB: 6R0S	Ki: 4400 (nM) from 1 assay(s)
EF2	BindingDB: 6R0S	IC50: 7800 (nM) from 1 assay(s)
JOH	BindingDB: 6R0S	Ki: 4.00e+4 (nM) from 1 assay(s)