4LSJ
Crystal Structure of the Glucocorticoid Receptor Ligand Binding Domain Bound to a Dibenzoxapine Sulfonamide
Summary for 4LSJ
| Entry DOI | 10.2210/pdb4lsj/pdb |
| Descriptor | Glucocorticoid receptor, D30 peptide, N-{3-[(1Z)-1-(10-methoxydibenzo[b,e]oxepin-11(6H)-ylidene)propyl]phenyl}methanesulfonamide, ... (4 entities in total) |
| Functional Keywords | nuclear hormone receptor, transcription |
| Biological source | Homo sapiens (human) More |
| Cellular location | Cytoplasm. Isoform Beta: Nucleus: P04150 |
| Total number of polymer chains | 2 |
| Total formula weight | 32388.69 |
| Authors | Carson, M.,Luz, J.G.,Clawson, D.,Coghlan, M. (deposition date: 2013-07-22, release date: 2014-01-29, Last modification date: 2024-02-28) |
| Primary citation | Carson, M.W.,Luz, J.G.,Suen, C.,Montrose, C.,Zink, R.,Ruan, X.,Cheng, C.,Cole, H.,Adrian, M.D.,Kohlman, D.T.,Mabry, T.,Snyder, N.,Condon, B.,Maletic, M.,Clawson, D.,Pustilnik, A.,Coghlan, M.J. Glucocorticoid receptor modulators informed by crystallography lead to a new rationale for receptor selectivity, function, and implications for structure-based design. J.Med.Chem., 57:849-860, 2014 Cited by PubMed Abstract: 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. PubMed: 24446728DOI: 10.1021/jm401616g PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.35 Å) |
Structure validation
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