期刊
NATURE CHEMICAL BIOLOGY
卷 4, 期 4, 页码 241-247出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.76
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资金
- NCI NIH HHS [5R01 CA89489, R01 CA018119-32, R01 CA089489-01A1, R01 CA089489-06A1, R01 CA089489-05S1, R33 CA132022, R01 CA089489-02, R01 CA089489-04, R01 CA089489-05, R01 CA37799, R01 CA037799-21, R01 CA089489-03, R01 CA018119, R01 CA089489-07, R01 CA089489, 5R01 CA18119, R01 CA037799] Funding Source: Medline
- NHLBI NIH HHS [R01 HL61432, R01 HL061432-04, R01 HL061432] Funding Source: Medline
- NIDDK NIH HHS [R01 DK077085-01A1, R37 DK015556, 5R37 DK15556, R37 DK015556-38, R01 DK077085, R01 DK015556] Funding Source: Medline
- NINDS NIH HHS [R21 NS056998-01, 1R21 NS056998-01, R21 NS056998] Funding Source: Medline
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 NF kappa B-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.
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