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https://hdl.handle.net/2440/75519
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Type: | Journal article |
Title: | NFκB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses |
Other Titles: | NFkappaB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses |
Author: | Nettles, K. Bruning, J. Gil, G. Nowak, J. Sharma, S. Hahm, J. Kulp, K. Hochberg, R. Zhou, H. Katzenellenbogen, J. Katzenellenbogen, B. Kim, Y. Joachimiak, A. Greene, G. |
Citation: | Nature Chemical Biology, 2008; 4(4):241-247 |
Publisher: | Nature Publishing Group |
Issue Date: | 2008 |
ISSN: | 1552-4450 1552-4469 |
Statement of Responsibility: | Kendall W Nettles, John B Bruning, German Gil, Jason Nowak, Sanjay K Sharma, Johnnie B Hahm, Kristen Kulp, Richard B Hochberg, Haibing Zhou, John A Katzenellenbogen, Benita S Katzenellenbogen, Younchang Kim, Andrzej Joachimiak & Geoffrey L Greene |
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. |
Keywords: | Humans Pyrazoles Pyrimidines NF-kappa B Receptors, Estrogen Ligands Crystallography, X-Ray Sensitivity and Specificity Signal Transduction Binding Sites Protein Conformation Protein Structure, Secondary Protein Folding Structure-Activity Relationship Mutation Hydrogen Bonding Models, Molecular Bridged Bicyclo Compounds |
Rights: | © 2008 Nature Publishing Group |
DOI: | 10.1038/nchembio.76 |
Published version: | http://dx.doi.org/10.1038/nchembio.76 |
Appears in Collections: | Aurora harvest Molecular and Biomedical Science publications |
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