A5078013348- Receptor Mechanisms and Signaling
- Protein Kinase Regulation and GTPase Signaling
- Metabolism, Diabetes, and Cancer
- Ion channel regulation and function
- Neuropeptides and Animal Physiology
- Pancreatic function and diabetes
- Diabetes Treatment and Management
- Cellular transport and secretion
- Bone health and treatments
- Mass Spectrometry Techniques and Applications
- Computational Drug Discovery Methods
- Biochemical and Molecular Research
- Malaria Research and Control
- Photoreceptor and optogenetics research
- Bone Metabolism and Diseases
- Bladder and Urothelial Cancer Treatments
- Parasitic Diseases Research and Treatment
- Cancer, Hypoxia, and Metabolism
- HIV Research and Treatment
- Enzyme Structure and Function
- HIV/AIDS drug development and treatment
- Tuberculosis Research and Epidemiology
- Cancer Research and Treatments
- Fibroblast Growth Factor Research
- PI3K/AKT/mTOR signaling in cancer
Butler University
2024-2025
University of Pittsburgh
2012-2024
Eli Lilly (United States)
2024
University of California, San Francisco
2023
Wood Hudson Cancer Research Laboratory
2018
The parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to calcium homeostasis and therapeutic target for osteoporosis hypoparathyroidism. Here we report the cryo-electron microscopy structure of human PTH1R bound long-acting PTH analog stimulatory protein. peptide adopts an extended helix with its amino terminus inserted deeply into transmembrane domain (TMD), which leads partial unwinding carboxyl 6 induces sharp kink at middle this allow couple In...
Loss of appetite, and even aversion to food, is a common experience during periods illness (e.g. infection pyrexia) and/or treatment chemotherapy). This responses distinct from the body’s homeostatic mechanisms (the hypothalamic leptin receptor-AGRP-POMC-MC4R axis), which normally regulate appetite weight gain in children, or maintenance adults. Previous work identified brainstem parabrachial nucleus as mediator suppression induced by anorectic hormones, amylin cholecystokinin. Here, authors...
Physiological responses to parathyroid hormone depend on the subcellular location of receptor activity.
Significance Blood Ca 2+ homeostasis is maintained by the actions of parathyroid hormone (PTH) on its cognate receptor PTHR. PTH binding to PTHR mediates prolonged adenosine 3′,5′-cyclic monophosphate (cAMP) responses in cells after internalization. Here, we show that extracellular prolongs residence time ligands receptor, consequently, increasing both duration activation and cAMP signaling. This positive allostery lost for mutant R25C, recently identified as a new cause hypocalcemia humans....
cAMP production upon activation of G s by protein-coupled receptors has classically been considered to be plasma membrane-delimited, but a shift in this paradigm occurred recent years with the identification several that continue signal from early endosomes after internalization. The molecular mechanisms regulating aspect signaling remain incompletely understood. Here, we investigated role q/11 parathyroid hormone (PTH) type 1 receptor (PTHR) mediating endosomal responses. Inhibition...
The continued emergence of antimalarial drug resistance highlights the need to develop new therapies. Unfortunately, development is often hampered by undesirable drug-like properties lead compounds. Prodrug approaches temporarily mask compound features, improving bioavailability and target penetration. We have found that lipophilic diester prodrugs phosphonic acid antibiotics, such as fosmidomycin (Fsm), exhibit significantly higher potency than their parent compounds [R.L. Edwards et al. ,...
In response to extracellular ligands, G protein-coupled receptors (GPCRs) undergo conformational changes that induce coupling intracellular effectors such as heterotrimeric proteins trigger various downstream signaling pathways 1. These events have been shown be highly regulated by the concerted effects of post-translational modifications (PTMs) occur in a ligand-dependent manner. Most notably, phosphorylation residues C-terminal cytoplasmic tail GPCRs has strongly implicated promoting...
The classical paradigm of G protein-coupled receptor (GPCR) signaling via proteins is grounded in a view that downstream responses are relatively transient and confined to the cell surface, but this notion has been revised recent years following identification several receptors engage sustained from subcellular compartments internalization ligand-receptor complex. This phenomenon was initially discovered for parathyroid hormone (PTH) type 1 (PTH1R), vital GPCR maintaining normal calcium...
The type-1 parathyroid hormone receptor (PTHR1), which regulates calcium homeostasis and tissue development, has two native agonists, (PTH) PTH-related protein (PTHrP). PTH forms a complex with the PTHR1 that is rapidly internalized induces prolonged cAMP production from endosomes. In contrast, PTHrP only transient production, primarily arises receptors on cell surface. We show backbone modification of PTH(1-34)-NH2 abaloparatide (a derivative) single homologous β-amino acid residue can...
The parathyroid hormone (PTH)–related protein (PTHrP) is indispensable for the development of mammary glands, placental calcium ion transport, tooth eruption, bone formation and remodeling, causes hypercalcemia in patients with malignancy. Although mature forms PTHrP body consist splice variants 139, 141, 173 amino acids, our current understanding on how endogenous transduces signals through its cognate G-protein coupled receptor (GPCR), PTH type 1 (PTHR), largely derived from studies done...
Orally bioavailable, synthetic nonpeptide agonists (NPAs) of the glucagon-like peptide-1 receptor (GLP-1R) may offer an effective, scalable pharmacotherapy to address metabolic disease epidemic. One first molecules in emerging class GLP-1R NPAs is orforglipron, which clinical development for treating type 2 diabetes and obesity. Here, we characterized pharmacological properties orforglipron comparison with peptide-based other NPAs. Competition binding experiments using either [ 125...
cAMP is a ubiquitous second messenger that regulates cellular proliferation, differentiation, attachment, migration, and several other processes. It has become increasingly evident tight regulation of accumulation localization confers divergent yet specific signaling to downstream pathways. Currently, few tools are available have sufficient spatial temporal resolution study location-biased signaling. Here, we introduce new fusion protein consisting light-activated adenylyl cyclase (bPAC)...
G protein-coupled receptors (GPCR) and glycosaminoglycans (GAGs) are two essential components of the cell surface that regulate physiological processes in body. GPCRs most extensive family transmembrane control cellular responses to extracellular stimuli, while GAGs polysaccharides contribute function matrix (ECM). Due their proximity plasma membrane, participate signal transduction by interacting with various molecules receptors. can directly interact certain or ligands (chemokines, peptide...
Purpose This study seeks an inexpensive, non-invasive, and easily reproducible measure of autonomic activity, which could greatly advance mind-body research treatment. Specific aims this were to: explore the utility selected physiological measures as a gauge function; confirm usefulness Stroop Math stressors; testing protocol for changes over time.
The continued emergence of antimalarial drug resistance highlights the need to develop new therapies. Unfortunately, development is often hampered by poor drug-like properties lead compounds. Prodrugging temporarily masks undesirable compound features, improving bioavailability and target penetration. We have found that lipophilic diester prodrugs phosphonic acid antibiotics, such as fosmidomycin, exhibit significantly higher potency than their parent compounds (1). However, activating...
Since it was proposed as a potential host-directed antiviral agent for SARS-CoV-2, the antiparasitic drug ivermectin has been investigated thoroughly in clinical trials, which have provided insufficient support its efficacy. To examine to be repurposed an agent, we therefore undertook series of preclinical studies. Consistent with early reports, decreased SARS-CoV-2 viral burden vitro models at low micromolar concentrations, five- ten-fold higher than reported toxic concentration. At similar...
Abstract The use of tumor-derived cultured cells continues to be a major resource for understanding the biological activities tumors and effects environmental factors pharmacological agents on tumors. With comparison data from International Cancer Genome Consortium Atlas comes realization that some frequently used lines may not closely share genomic similarity with patient tumors, whereas less cell high similarity. For example, bladder cancer line T24 (HTB-4) is more than other lines. We...
The parathyroid hormone (PTH) type 1 receptor (PTHR) serves as the cognate for two endogenous ligands, PTH and its related peptide (PTHrP). Binding of PTHrP to PTHR results in only transient cAMP production that is limited plasma membrane, while induces sustained responses derived from endosomes following internalization ligand-receptor complex. underlying mechanism regulation these kinetically-distinct signaling events are poorly understood. Here we show extracellular Ca2+ acts a positive...
The parathyroid hormone (PTH) type 1 receptor (PTHR) serves as the cognate for two endogenous ligands, PTH and its related peptide (PTHrP). Binding of PTHrP to PTHR results in only transient cAMP production that is limited plasma membrane, while induces sustained responses derived from endosomes following internalization ligand‐receptor complex. underlying mechanism regulation these kinetically‐distinct signaling events are poorly understood. Here we show extracellular Ca 2+ acts a positive...