4IWC

Crystal Structure of the Estrogen Receptor alpha Ligand-binding Domain in Complex with a Dynamic Thiophene-derivative

Summary for 4IWC

• Entry DOI: 10.2210/pdb4iwc/pdb
• Related: 4IU7 4IUI 4IV2 4IV4 4IVW 4IVY 4IW6 4IW8 4IWF
• Descriptor: Estrogen receptor, Nuclear receptor coactivator 2, 4,4'-thiene-2,5-diylbis(3-methylphenol), ... (4 entities in total)
• Functional Keywords: nuclear hormone receptor, transcription factor, ligand-binding, nucleus, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 59524.28

Authors

Nwachukwu, J.C.,Srinivasan, S.,Parent, A.A.,Cavett, V.,Nowak, J.,Hughes, T.S.,Kojetin, D.J.,Katzenellenbogen, J.A.,Nettles, K.W. (deposition date: 2013-01-23, release date: 2013-03-27, Last modification date: 2023-09-20)

Primary citation

Srinivasan, S.,Nwachukwu, J.C.,Parent, A.A.,Cavett, V.,Nowak, J.,Hughes, T.S.,Kojetin, D.J.,Katzenellenbogen, J.A.,Nettles, K.W.
Ligand binding dynamics rewire cellular signaling via Estrogen Receptor-alpha
Nat.Chem.Biol., 9:326-332, 2013

PubMed Abstract: Ligand-binding dynamics control allosteric signaling through the estrogen receptor-α (ERα), but the biological consequences of such dynamic binding orientations are unknown. Here, we compare a set of ER ligands having dynamic binding orientation (dynamic ligands) with a control set of isomers that are constrained to bind in a single orientation (constrained ligands). Proliferation of breast cancer cells directed by constrained ligands is associated with DNA binding, coactivator recruitment and activation of the estrogen-induced gene GREB1, reflecting a highly interconnected signaling network. In contrast, proliferation driven by dynamic ligands is associated with induction of ERα-mediated transcription in a DNA-binding domain (DBD)-dependent manner. Further, dynamic ligands showed enhanced anti-inflammatory activity. The DBD-dependent profile was predictive of these signaling patterns in a larger diverse set of natural and synthetic ligands. Thus, ligand dynamics directs unique signaling pathways and reveals a new role of the DBD in allosteric control of ERα-mediated signaling.

PubMed: 23524984
DOI: 10.1038/nchembio.1214

Experimental method

X-RAY DIFFRACTION (2.24 Å)