4LSJ

Crystal Structure of the Glucocorticoid Receptor Ligand Binding Domain Bound to a Dibenzoxapine Sulfonamide

4LSJ の概要

• エントリーDOI: 10.2210/pdb4lsj/pdb
• 分子名称: Glucocorticoid receptor, D30 peptide, N-{3-[(1Z)-1-(10-methoxydibenzo[b,e]oxepin-11(6H)-ylidene)propyl]phenyl}methanesulfonamide, ... (4 entities in total)
• 機能のキーワード: nuclear hormone receptor, transcription
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cytoplasm. Isoform Beta: Nucleus: P04150
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32388.69

構造登録者

Carson, M.,Luz, J.G.,Clawson, D.,Coghlan, M. (登録日: 2013-07-22, 公開日: 2014-01-29, 最終更新日: 2024-02-28)

主引用文献

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

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: 24446728
DOI: 10.1021/jm401616g

実験手法

X-RAY DIFFRACTION (2.35 Å)