NFκB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses

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 Joachmiak, Geoffrey L. Greene

Research output: Contribution to journalArticle

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 NFκB-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.

Original languageEnglish (US)
Pages (from-to)241-247
Number of pages7
JournalNature chemical biology
Volume4
Issue number4
DOIs
StatePublished - Apr 2008

Fingerprint

Estrogen Receptors
Steroid Receptors
Crystallization
Ligands
Hormones
Protein Folding
Steroids
Pharmacology
Gene Expression
Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Nettles, K. W., Bruning, J. B., Gil, G., Nowak, J., Sharma, S. K., Hahm, J. B., ... Greene, G. L. (2008). NFκB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses. Nature chemical biology, 4(4), 241-247. https://doi.org/10.1038/nchembio.76

NFκB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses. / Nettles, Kendall W.; Bruning, John B.; Gil, German; Nowak, Jason; Sharma, Sanjay K.; Hahm, Johnnie B.; Kulp, Kristen; Hochberg, Richard B.; Zhou, Haibing; Katzenellenbogen, John A.; Katzenellenbogen, Benita S; Kim, Younchang; Joachmiak, Andrzej; Greene, Geoffrey L.

In: Nature chemical biology, Vol. 4, No. 4, 04.2008, p. 241-247.

Research output: Contribution to journalArticle

Nettles, KW, Bruning, JB, Gil, G, Nowak, J, Sharma, SK, Hahm, JB, Kulp, K, Hochberg, RB, Zhou, H, Katzenellenbogen, JA, Katzenellenbogen, BS, Kim, Y, Joachmiak, A & Greene, GL 2008, 'NFκB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses', Nature chemical biology, vol. 4, no. 4, pp. 241-247. https://doi.org/10.1038/nchembio.76
Nettles, Kendall W. ; Bruning, John B. ; Gil, German ; Nowak, Jason ; Sharma, Sanjay K. ; Hahm, Johnnie B. ; Kulp, Kristen ; Hochberg, Richard B. ; Zhou, Haibing ; Katzenellenbogen, John A. ; Katzenellenbogen, Benita S ; Kim, Younchang ; Joachmiak, Andrzej ; Greene, Geoffrey L. / NFκB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses. In: Nature chemical biology. 2008 ; Vol. 4, No. 4. pp. 241-247.
@article{ba8a09894fb74d389c4f34d27c4958c1,
title = "NFκB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses",
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 NFκB-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.",
author = "Nettles, {Kendall W.} and Bruning, {John B.} and German Gil and Jason Nowak and Sharma, {Sanjay K.} and Hahm, {Johnnie B.} and Kristen Kulp and Hochberg, {Richard B.} and Haibing Zhou and Katzenellenbogen, {John A.} and Katzenellenbogen, {Benita S} and Younchang Kim and Andrzej Joachmiak and Greene, {Geoffrey L.}",
year = "2008",
month = "4",
doi = "10.1038/nchembio.76",
language = "English (US)",
volume = "4",
pages = "241--247",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - NFκB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses

AU - Nettles, Kendall W.

AU - Bruning, John B.

AU - Gil, German

AU - Nowak, Jason

AU - Sharma, Sanjay K.

AU - Hahm, Johnnie B.

AU - Kulp, Kristen

AU - Hochberg, Richard B.

AU - Zhou, Haibing

AU - Katzenellenbogen, John A.

AU - Katzenellenbogen, Benita S

AU - Kim, Younchang

AU - Joachmiak, Andrzej

AU - Greene, Geoffrey L.

PY - 2008/4

Y1 - 2008/4

N2 - 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 NFκB-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.

AB - 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 NFκB-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.

UR - http://www.scopus.com/inward/record.url?scp=40949084787&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=40949084787&partnerID=8YFLogxK

U2 - 10.1038/nchembio.76

DO - 10.1038/nchembio.76

M3 - Article

C2 - 18344977

AN - SCOPUS:40949084787

VL - 4

SP - 241

EP - 247

JO - Nature Chemical Biology

JF - Nature Chemical Biology

SN - 1552-4450

IS - 4

ER -