5G3J

Discovery of New Selective Glucocorticoid Receptor Agonist Leads

PDB DOI: https://doi.org/10.2210/pdb5G3J/pdb

Classification: DNA BINDING PROTEIN
Organism(s): Homo sapiens
Expression System: Trichoplusia ni
Mutation(s): Yes

Deposited: 2016-04-27 Released: 2017-02-15
Deposition Author(s): Berger, M., Edman, K., Wissler, L., Neuhaus, R., Rehwinkel, H., Schacke, H., Jaroch, S.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.40 Å
R-Value Free: 0.235
R-Value Work: 0.197
R-Value Observed: 0.198

Starting Model: experimental
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Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Discovery of New Selective Glucocorticoid Receptor Agonist Leads.

Berger, M., Rehwinkel, H., Schmees, N., Schacke, H., Edman, K., Wissler, L., Reichel, A., Jaroch, S.

(2017) Bioorg Med Chem Lett 27: 437

PubMed: 28043796 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2016.12.047
Primary Citation of Related Structures:
5G3J

PubMed Abstract:
We report on the discovery of two new lead series for the development of glucocorticoid receptor agonists. Firstly, the discovery of tetrahydronaphthalenes led to metabolically stable and dissociated compounds. Their binding mode to the glucocorticoid receptor could be elucidated through an X-ray structure. Closer inspection into the reaction path and analyses of side products revealed a new amino alcohol series also addressing the glucocorticoid receptor and demonstrating strong anti-inflammatory activity in vitro.

Organizational Affiliation

Medicinal Chemistry Berlin, Candidate Generation & External Innovation, Drug Discovery, Bayer Pharma AG, D-13353 Berlin, Germany. Electronic address: [email protected].

Macromolecule Content

Total Structure Weight: 35.03 kDa
Atom Count: 2,279
Modelled Residue Count: 261
Deposited Residue Count: 294
Unique protein chains: 2

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
GLUCOCORTICOID RECEPTOR	A	280	Homo sapiens	Mutation(s): 4
UniProt & NIH Common Fund Data Resources
Find proteins for P04150 (Homo sapiens) Explore P04150 Go to UniProtKB: P04150
PHAROS: P04150 GTEx: ENSG00000113580
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P04150
Sequence Annotations Expand
Reference Sequence

Find similar proteins by: Sequence | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
NUCLEAR RECEPTOR COACTIVATOR 2	B	14	Homo sapiens	Mutation(s): 0
UniProt & NIH Common Fund Data Resources
Find proteins for Q15596 (Homo sapiens) Explore Q15596 Go to UniProtKB: Q15596
PHAROS: Q15596 GTEx: ENSG00000140396
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q15596
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
CPS Query on CPS Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE C₃₂ H₅₈ N₂ O₇ S UMCMPZBLKLEWAF-BCTGSCMUSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
E7T Query on E7T Download Ideal Coordinates CCD File SDF format, chain E [auth A] MOL2 format, chain E [auth A] mmCIF format, chain E [auth A]	E [auth A]	5-[[(1S,2R,4R)-4-ethyl-6,7-bis(fluoranyl)-2,5-bis(oxidanyl)-2-(trifluoromethyl)-3,4-dihydro-1H-naphthalen-1-yl]amino]-1H-quinolin-2-one C₂₂ H₁₉ F₅ N₂ O₃ VZPLUSXTJULLCS-SYQZRHMFSA-N		Interactions Focus chain E [auth A] Interactions & Density Focus chain E [auth A]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A] mmCIF format, chain D [auth A]	D [auth A]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
E7T	BindingDB: 5G3J	IC50: min: 1.2, max: 63 (nM) from 4 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.40 Å
R-Value Free: 0.235
R-Value Work: 0.197
R-Value Observed: 0.198
Space Group: P 3₂ 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 84.263	α = 90
b = 84.263	β = 90
c = 106.678	γ = 120

Software Package:

Software Name	Purpose
BUSTER	refinement
MOSFLM	data reduction
SCALA	data scaling
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2017-02-15

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2017-02-15
Type: Initial release
Version 1.1: 2017-08-23
Changes: Data collection
Version 1.2: 2019-04-03
Changes: Data collection, Source and taxonomy
Version 1.3: 2024-01-10
Changes: Data collection, Database references, Derived calculations, Other, Refinement description