2QA8

Crystal Structure of the Estrogen Receptor Alpha Ligand Binding Domain Mutant 537S Complexed with Genistein

Summary for 2QA8

• Entry DOI: 10.2210/pdb2qa8/pdb
• Related: 2QA6 2QAB
• Descriptor: Estrogen receptor, nuclear receptor coactivator 2, GENISTEIN, ... (5 entities in total)
• Functional Keywords: protein-ligand complex, transcription
• Biological source: Homo sapiens (human); More
• Cellular location: Isoform 1: Nucleus. Isoform 3: Nucleus: P03372 Q8BN74
• Total number of polymer chains: 4
• Total formula weight: 62625.66

Authors

Nettles, K.W.,Bruning, J.B.,Nowak, J.,Sharma, S.K.,Hahm, J.B.,Shi, Y.,Kulp, K.,Hochberg, R.B.,Zhou, H.,Katzenellenbogen, J.A.,Katzenellenbogen, B.S.,Kim, Y.,Joachmiak, A.,Greene, G.L. (deposition date: 2007-06-14, release date: 2008-03-18, Last modification date: 2024-10-16)

Primary citation

Nettles, K.W.,Bruning, J.B.,Gil, G.,Nowak, J.,Sharma, S.K.,Hahm, J.B.,Kulp, K.,Hochberg, R.B.,Zhou, H.,Katzenellenbogen, J.A.,Katzenellenbogen, B.S.,Kim, Y.,Joachmiak, A.,Greene, G.L.
NFkappaB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses
Nat.Chem.Biol., 4:241-247, 2008

PubMed Abstract: Our understanding of how steroid hormones regulate physiological functions has been significantly advanced by structural biology approaches. However, progress has been hampered by misfolding of the ligand binding domains in heterologous expression systems and by conformational flexibility that interferes with crystallization. Here, we show that protein folding problems that are common to steroid hormone receptors are circumvented by mutations that stabilize well-characterized conformations of the receptor. We use this approach to present the structure of an apo steroid receptor that reveals a ligand-accessible channel allowing soaking of preformed crystals. Furthermore, crystallization of different pharmacological classes of compounds allowed us to define the structural basis of NFkappaB-selective signaling through the estrogen receptor, thus revealing a unique conformation of the receptor that allows selective suppression of inflammatory gene expression. The ability to crystallize many receptor-ligand complexes with distinct pharmacophores allows one to define structural features of signaling specificity that would not be apparent in a single structure.

PubMed: 18344977
DOI: 10.1038/nchembio.76

Experimental method

X-RAY DIFFRACTION (1.85 Å)