Predictive features of ligand-specific signaling through the estrogen receptor.
Some estrogen receptor-α (ERα)-targeted breast cancer therapies such as tamoxifen have tissue-selective or cell-specific activities, while others have similar activities in different cell types. To identify biophysical determinants of cell-specific signaling and breast cancer cell proliferation, we synthesized 241 ERα ligands based on 19 chemical scaffolds, and compared ligand response using quantitative bioassays for canonical ERα activities and X-ray crystallography. Ligands that regulate the dynamics and stability of the coactivator-binding site in the C-terminal ligand-binding domain, called activation function-2 (AF-2), showed similar activity profiles in different cell types. Such ligands induced breast cancer cell proliferation in a manner that was predicted by the canonical recruitment of the coactivators NCOA1/2/3 and induction of the GREB1 proliferative gene. For some ligand series, a single inter-atomic distance in the ligand-binding domain predicted their proliferative effects. In contrast, the N-terminal coactivator-binding site, activation function-1 (AF-1), determined cell-specific signaling induced by ligands that used alternate mechanisms to control cell proliferation. Thus, incorporating systems structural analyses with quantitative chemical biology reveals how ligands can achieve distinct allosteric signaling outcomes through ERα.
Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL, USA.
Jerome C
http://orcid.org/0000-0003-4313-9187
JC
Nwachukwu
Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL, USA.
Sathish
S
Srinivasan
State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, China.
Yangfan
Y
Zheng
State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, China.
Song
S
Wang
Department of Chemistry, University of Illinois, Urbana, IL, USA.
Jian
J
Min
State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, China.
Chune
C
Dong
State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, China.
Zongquan
Z
Liao
Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL, USA.
Jason
J
Nowak
Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL, USA.
Nicholas J
NJ
Wright
PamGene International, Den Bosch, The Netherlands.
René
R
Houtman
Department of Chemistry, University of Illinois, Urbana, IL, USA.
Kathryn E
KE
Carlson
Department of Chemistry, Virginia Tech, Blacksburg, VA, USA.
Jatinder S
JS
Josan
Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA.
Olivier
O
Elemento
Department of Chemistry, University of Illinois, Urbana, IL, USA knettles@scripps.edu jkatzene@illinois.edu zhouhb@whu.edu.cn.
John A
JA
Katzenellenbogen
State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, China knettles@scripps.edu jkatzene@illinois.edu zhouhb@whu.edu.cn.
Hai-Bing
HB
Zhou
Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL, USA knettles@scripps.edu jkatzene@illinois.edu zhouhb@whu.edu.cn.
Kendall W
http://orcid.org/0000-0003-2917-7574
KW
Nettles
D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D019151:Peptide Library; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects*
D047628:Estrogen Receptor alpha; D008024:Ligands; D019151:Peptide Library
Breast cancer; Chemical biology; Crystal structure; Nuclear receptor; Signal transduction