4LSJ: Crystal Structure Of The Glucocorticoid Receptor Ligand Binding Domain Bound To A Dibenzoxapine Sulfonamide

The structural basis of the pharmacology enabling the use of glucocorticoids as reliable treatments for inflammation and autoimmune diseases has been augmented with a new group of glucocorticoid receptor (GR) ligands. Compound 10, the archetype of a new family of dibenzoxepane and dibenzosuberane sulfonamides, is a potent anti-inflammatory agent with selectivity for the GR versus other steroid receptors and a differentiated gene expression profile versus clinical glucocorticoids (lower GR transactivation with comparable transrepression). A stereospecific synthesis of this chiral molecule provides the unique topology needed for biological activity and structural biology. In vivo activity of 10 in acute and chronic models of inflammation is equivalent to prednisolone. The crystal structure of compound 10 within the GR ligand binding domain (LBD) unveils a novel binding conformation distinct from the classic model adopted by cognate ligands. The overall conformation of the GR LBD/10 complex provides a new basis for binding, selectivity, and anti-inflammatory activity and a path for further insights into structure-based ligand design.
PDB ID: 4LSJDownload
MMDB ID: 117059
PDB Deposition Date: 2013/7/22
Updated in MMDB: 2014/03
Experimental Method:
x-ray diffraction
Resolution: 2.35  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 4LSJ: tetrameric; determined by author and by software (PISA)
Molecular Components in 4LSJ
Label Count Molecule
Proteins (4 molecules)
Glucocorticoid Receptor(Gene symbol: NR3C1)
Molecule annotation
D30 Peptide
Molecule annotation
Chemicals (4 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB