4CSJ

The discovery of potent selective glucocorticoid receptor modulators, suitable for inhalation

PDB DOI: https://doi.org/10.2210/pdb4CSJ/pdb

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

Deposited: 2014-03-07 Released: 2014-05-07
Deposition Author(s): Edman, K., Ahlgren, R., Bengtsson, M., Bladh, H., Backstrom, S., Dahmen, J., Henriksson, K., Hillertz, P., Hulikal, V., Jerre, A., Kinchin, L., Kase, C., Lepisto, M., Mile, I., Nilsson, S., Smailagic, A., Taylor, J., Tjornebo, A., Wissler, L., Hansson, T.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.30 ?
R-Value Free: 0.234
R-Value Work: 0.218
R-Value Observed: 0.219

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

The Discovery of Potent and Selective Non-Steroidal Glucocorticoid Receptor Modulators, Suitable for Inhalation.

Edman, K., Ahlgren, R., Bengtsson, M., Bladh, H., Backstrom, S., Dahmen, J., Henriksson, K., Hillertz, P., Hulikal, V., Jerre, A., Kinchin, L., Kase, C., Lepisto, M., Mile, I., Nilsson, S., Smailagic, A., Taylor, J., Tjornebo, A., Wissler, L., Hansson, T.

(2014) Bioorg Med Chem Lett 24: 2571

PubMed: 24755427 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2014.03.070
Primary Citation of Related Structures:
4CSJ

PubMed Abstract:
We report the discovery of highly potent and selective non-steroidal glucocorticoid receptor modulators with PK properties suitable for inhalation. A high throughput screen of the AstraZeneca compound collection identified sulfonamide 3 as a potent non-steroidal glucocorticoid receptor ligand. Further optimization of this lead generated indazoles 30 and 48 that were progressed to characterization in in vivo models. X-ray crystallography was used to gain further insight into the binding mode of selected ligands.

Organizational Affiliation

Discovery Sciences, Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 M?lndal, Sweden.

Macromolecule Content

Total Structure Weight: 34.3 kDa
Atom Count: 2,273
Modelled Residue Count: 260
Deposited Residue Count: 293
Unique protein chains: 2

Macromolecules

Find similar proteins by:

(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	13	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 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NN7 Query on NN7 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]	N-[(2S)-1-[[1-(4-fluorophenyl)indazol-4-yl]amino]propan-2-yl]-2,4,6-trimethyl-benzenesulfonamide C₂₅ H₂₇ F N₄ O₂ S NMWIJNGJMPMFQG-IBGZPJMESA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
EDO Query on EDO 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]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
NN7	BindingDB: 4CSJ	IC50: min: 0.9, max: 14 (nM) from 4 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.30 ?
R-Value Free: 0.234
R-Value Work: 0.218
R-Value Observed: 0.219
Space Group: P 3₂ 2 1

Unit Cell:

Length ( ? )	Angle ( ? )
a = 84.354	α = 90
b = 84.354	β = 90
c = 105.669	γ = 120

Software Package:

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

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2014-05-07

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2014-05-07
Type: Initial release
Version 1.1: 2014-05-21
Changes: Database references
Version 1.2: 2023-12-20
Changes: Data collection, Database references, Derived calculations, Other, Refinement description