Amino acid sequence of the AhR1 ligand-binding domain predicts avian sensitivity to dioxin like compounds: In vivo verification in European starlings

2014 ◽  
Vol 33 (12) ◽  
pp. 2753-2758 ◽  
Author(s):  
Margaret L. Eng ◽  
John E. Elliott ◽  
Stephanie P. Jones ◽  
Tony D. Williams ◽  
Ken G. Drouillard ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Ligand Binding ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
European Starlings

scholarly journals A Novel Ligand-binding Domain Involved in Regulation of Amino Acid Metabolism in Prokaryotes

2002 ◽  
Vol 277 (40) ◽  
pp. 37464-37468 ◽  
Author(s):  
Thijs J. G. Ettema ◽  
Arie B. Brinkman ◽  
Travis H. Tani ◽  
John B. Rafferty ◽  
John van der Oost
Keyword(s):  
Amino Acid ◽  
Ligand Binding ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Binding Domain ◽  
Ligand Binding Domain

scholarly journals Peptide Vaccines and Peptidomimetics of EGFR (HER-1) Ligand Binding Domain Inhibit Cancer Cell Growth In Vitro and In Vivo

2013 ◽  
Vol 191 (1) ◽  
pp. 217-227 ◽  
Author(s):  
Kevin Chu Foy ◽  
Ruthie M. Wygle ◽  
Megan J. Miller ◽  
Jay P. Overholser ◽  
Tanios Bekaii-Saab ◽  
...  
Keyword(s):  
Cell Growth ◽  
Ligand Binding ◽  
Cancer Cell ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Peptide Vaccines ◽  
Cancer Cell Growth

scholarly journals Transmembrane signaling in the sensor kinase DcuS ofEscherichia coli: A long-range piston-type displacement of transmembrane helix 2

2015 ◽  
Vol 112 (35) ◽  
pp. 11042-11047 ◽  
Author(s):  
Christian Monzel ◽  
Gottfried Unden
Keyword(s):  
Amino Acid ◽  
Ligand Binding ◽  
Transmembrane Helix ◽  
Binding Domain ◽  
Cross Linking ◽  
Sensor Kinase ◽  
Amino Acid Residues ◽  
Terminal Part ◽  
Type Shift

The C4-dicarboxylate sensor kinase DcuS is membrane integral because of the transmembrane (TM) helices TM1 and TM2. Fumarate-induced movement of the helices was probed in vivo by Cys accessibility scanning at the membrane–water interfaces after activation of DcuS by fumarate at the periplasmic binding site. TM1 was inserted with amino acid residues 21–41 in the membrane in both the fumarate-activated (ON) and inactive (OFF) states. In contrast, TM2 was inserted with residues 181–201 in the OFF state and residues 185–205 in the ON state. Replacement of Trp 185 by an Arg residue caused displacement of TM2 toward the outside of the membrane and a concomitant induction of the ON state. Results from Cys cross-linking of TM2/TM2′ in the DcuS homodimer excluded rotation; thus, data from accessibility changes of TM2 upon activation, either by ligand binding or by mutation of TM2, and cross-linking of TM2 and the connected region in the periplasm suggest a piston-type shift of TM2 by four residues to the periplasm upon activation (or fumarate binding). This mode of function is supported by the suggestion from energetic calculations of two preferred positions for TM2 insertion in the membrane. The shift of TM2 by four residues (or 4–6 Å) toward the periplasm upon activation is complementary to the periplasmic displacement of 3–4 Å of the C-terminal part of the periplasmic ligand-binding domain upon ligand occupancy in the citrate-binding domain in the homologous CitA sensor kinase.

Effect of ligand binding domain activating mutations of ESR1 on cellular metabolism, liver tropism, and chemotherapy resistance.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14506-e14506
Author(s):  
Ido Wolf ◽  
Lotem Zinger ◽  
Keren Merenbakh-Lamin ◽  
Anat Klein Goldberg ◽  
Adi Elazar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ligand Binding ◽  
Cell Metabolism ◽  
Chemotherapy Resistance ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Aggressive Phenotype ◽  
Activating Mutations ◽  
Metabolic Activities

e14506 Background: Mutations in the ligand binding domain (LBD) of estrogen receptor α (ER) confer constitutive transcriptional activity and resistance to endocrine therapies in breast cancer patients. Accumulating clinical data suggest adverse outcome for patients harboring tumors expressing these mutations. We aimed to elucidate mechanisms conferring this aggressive phenotype. Methods: Cells constitutively expressing physiologic levels of ER harboring activating LBD mutations were generated and characterized for viability, invasiveness and tumor formation in vivo. Gene expression profile was studied using RNAseq. Metabolic properties were assessed using global metabolite screen and direct measurement of metabolic activity. Response to chemotherapies was assessed using viability assays. Results: Cells expressing mutated ER showed increased proliferation, migration and in vivo tumorogenicity compared to cells expressing the WT-ER, even in the presence of estrogen. Experiments in mice revealed a more aggressive phenotype of the Y537S mutant compared to D538G as well as unique tissue predilection. Thus, 538G-ER cells exhibited liver tropism while Y537-ER cells mainly metastasized to the lungs and lymph nodes. Importantly, both mutations conferred resistance to paclitaxel and doxorubicin. Further studies indicated association of the mutated ER with upregulation of genes involved in tumor cell metabolism. Indeed, a global metabolic screen revealed distinct metabolic profile for cells harboring activating mutations, including the ability to utilize glutamine as an alternative carbon source. Moreover, we observed unique metabolic activities enabling cells to thrive in urea-reach environment of the liver, and overcome doxorubicin-induced stress responses. Conclusions: Taken together, these data indicate estrogen-independent rewiring of breast cancer cell metabolism by LBD-activating mutations, enabling aggressivene clinical behavior and chemotherapy resistance. Importantly, These unique metabolic activities may serve as a potential vulnerability and aid in the development of novel treatment strategies to overcome endocrine resistance.

scholarly journals Polyamines Modulate the Interaction between Nuclear Receptors and Vitamin D Receptor-Interacting Protein 205

2002 ◽  
Vol 16 (7) ◽  
pp. 1502-1510 ◽  
Author(s):  
Yutaka Maeda ◽  
Christophe Rachez ◽  
Leo Hawel ◽  
Craig V. Byus ◽  
Leonard P. Freedman ◽  
...  
Keyword(s):  
Vitamin D ◽  
Ligand Binding ◽  
Nuclear Receptors ◽  
Vitamin D Receptor ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Full Length ◽  
Dependent Manner ◽  
Interacting Protein

Abstract Nuclear receptors (NR) activate transcription by interacting with several different coactivator complexes, primarily via LXXLL motifs (NR boxes) of the coactivator that bind a common region in the ligand binding domain of nuclear receptors (activation function-2, AF–2) in a ligand-dependent fashion. However, how nuclear receptors distinguish between different sets of coactivators remains a mystery, as does the mechanism by which orphan receptors such as hepatocyte nuclear factor 4α (HNF4α) activate transcription. In this study, we show that HNF4α interacts with a complex containing vitamin D receptor (VDR)-interacting proteins (DRIPs) in the absence of exogenously added ligand. However, whereas a full-length DRIP205 construct enhanced the activation by HNF4α in vivo, it did not interact well with the HNF4α ligand binding domain in vitro. In investigating this discrepancy, we found that the polyamine spermine significantly enhanced the interaction between HNF4α and full-length DRIP205 in an AF-2, NR-box-dependent manner. Spermine also enhanced the interaction of DRIP205 with the VDR even in the presence of its ligand, but decreased the interaction of both HNF4α and VDR with the p160 coactivator glucocorticoid receptor interacting protein 1 (GR1P1). We also found that GR1P1 and DRIP205 synergistically activated HNF4α-mediated transcription and that a specific inhibitor of polyamine biosynthesis, α-difluoromethylornithine (DFMO), decreased the ability of HNF4α to activate transcription in vivo. These results lead us to propose a model in which polyamines may facilitate the switch between different coactivator complexes binding to NRs.

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