A5037357686- Estrogen and related hormone effects
- Synthesis and biological activity
- Computational Drug Discovery Methods
- Bioactive Compounds and Antitumor Agents
- Free Radicals and Antioxidants
- Ferrocene Chemistry and Applications
- Peroxisome Proliferator-Activated Receptors
- Retinoids in leukemia and cellular processes
- Chemical Synthesis and Analysis
- Receptor Mechanisms and Signaling
- Adipose Tissue and Metabolism
- Organic Chemistry Cycloaddition Reactions
- Cytokine Signaling Pathways and Interactions
- NF-κB Signaling Pathways
- Synthesis and Characterization of Heterocyclic Compounds
- Genomics, phytochemicals, and oxidative stress
- Inflammatory mediators and NSAID effects
- Steroid Chemistry and Biochemistry
- Crystallization and Solubility Studies
- Synthesis of Tetrazole Derivatives
- Hormonal Regulation and Hypertension
- X-ray Diffraction in Crystallography
- Mitochondrial Function and Pathology
- Metal complexes synthesis and properties
- interferon and immune responses
Scripps Research Institute
2016-2025
The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
2015-2024
University of Florida
2022-2024
Scripps (United States)
2015-2023
Scripps College
2015
Scripps Institution of Oceanography
2015
University of Chicago
1996-2007
Joint Center for Structural Genomics
2006
Argonne National Laboratory
2006
University of Illinois Urbana-Champaign
2006
The estrogen-dependent inflammatory and neuroangiogenic activities that drive endometriosis can be suppressed by estrogen receptor ligands in mice.
Resveratrol has beneficial effects on aging, inflammation and metabolism, which are thought to result from activation of the lysine deacetylase, sirtuin 1 (SIRT1), cAMP pathway, or AMP-activated protein kinase. In this study, we report that resveratrol acts as a pathway-selective estrogen receptor-α (ERα) ligand modulate inflammatory response but not cell proliferation. A crystal structure ERα ligand-binding domain (LBD) complex with revealed unique perturbation coactivator-binding surface,...
Abstract A subset of nuclear receptors (NRs) function as obligate heterodimers with retinoid X receptor (RXR), allowing integration ligand-dependent signals across the dimer interface via an unknown structural mechanism. Using magnetic resonance (NMR) spectroscopy, x-ray crystallography and hydrogen/deuterium exchange (HDX) mass spectrometry, here we show allosteric mechanism through which RXR co-operates a permissive partner, peroxisome proliferator-activated (PPAR)-γ, while rendered...
Glucocorticoids (GCs) are potent repressors of NF-κB activity, making them a preferred choice for treatment inflammation-driven conditions. Despite the widespread use GCs in clinic, current models inadequate to explain role glucocorticoid receptor (GR) within this critical signaling pathway. GR binding directly itself-tethering DNA binding-independent manner-represents standing model how inhibit NF-κB-driven transcription. We demonstrate that direct genomic response elements (κBREs) mediates...
Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERα)) gene ligand-binding domain (LBD) represent recognized mechanism of acquired resistance. Antiestrogens with improved efficacy versus tamoxifen might overcome resistant phenotype ER +breast cancers. Bazedoxifene (BZA) is potent antiestrogen that clinically approved use hormone replacement therapies. We found BZA possesses...
Abstract Hydroxychloroquine (HCQ), a drug used to treat lupus and malaria, was proposed as treatment for SARS-coronavirus-2 (SARS-CoV-2) infection, albeit with controversy. In vitro, HCQ effectively inhibits viral entry, but its use in the clinic has been hampered by conflicting results. A better understanding of HCQ’s mechanism actions vitro is needed. Recently, anesthetics were shown disrupt ordered clusters monosialotetrahexosylganglioside1 (GM1) lipid. These same lipid recruit SARS-CoV-2...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein binds angiotensin-converting enzyme as its primary infection mechanism. Interactions between S and endogenous proteins occur after but are not well understood. We profiled binding of against >9000 human found an interaction estrogen receptor α (ERα). Using bioinformatics, supercomputing, experimental assays, we identified a highly conserved functional nuclear coregulator (NRC) LXD-like motif on the S2...
The glucocorticoid receptor (GR) is a ligand-regulated transcription factor that controls the expression of extensive gene networks, driving both up- and down-regulation. GR utilizes multiple DNA-binding-dependent -independent mechanisms to achieve context-specific transcriptional outcomes. DNA-binding-independent mechanism involves tethering pro-inflammatory activator protein-1 (AP-1) through protein-protein interactions. This has served as predominant model GR-mediated transrepression...
Abstract Many estrogen receptor α (ERα)–positive breast cancers develop resistance to endocrine therapy via mutation of ERs whose constitutive activation is associated with shorter patient survival. Because there now a clinical need for new antiestrogens (AE) against these mutant ERs, we describe here our development and characterization three chemically novel AEs that effectively suppress proliferation cancer cells tumors. Our are effective wild-type Y537S D538G the two most commonly...
Abstract Some estrogen receptor‐α ( ER α)‐targeted breast cancer therapies such as tamoxifen have tissue‐selective or cell‐specific activities, while others similar activities in different cell types. To identify biophysical determinants of signaling and proliferation, we synthesized 241 α ligands based on 19 chemical scaffolds, compared ligand response using quantitative bioassays for canonical X‐ray crystallography. Ligands that regulate the dynamics stability coactivator‐binding site...
Significance To address the unmet clinical need for effectively suppressing estrogen receptor (ER) activity with both de novo resistance and in advanced ER-positive breast cancers that are resistant to standard-of-care antiestrogens, we have developed dual-mechanism ER inhibitors (DMERIs) employ two distinct ER-targeting moieties. These DMERI elicited noncanonical structural perturbations of ligand-binding domain stabilized multiple antagonist substates within dimer generate highly...
To probe the importance of heterocyclic core estrogen receptor (ER) ligands, we prepared a series thiophene-core ligands by Suzuki cross-coupling aryl boronic acids with bromo-thiophenes and assessed their binding cell biological activities. The disposition phenol substituents on thiophene core, at alternate or adjacent sites, nature these phenols, all contribute to affinity subtype selectivity. Most bis(hydroxyphenyl)-thiophenes were ERβ selective, whereas tris(hydroxyphenyl)-thiophenes ERα...