Scholars@Duke
Alem W Kahsai

Alem W Kahsai

Assistant Professor in Medicine
Medicine, Cardiology

Selected Publications

Role of the V2R-βarrestin-Gβγ complex in promoting G protein translocation to endosomes.

Journal Article Commun Biol · July 7, 2024 Classically, G protein-coupled receptors (GPCRs) promote signaling at the plasma membrane through activation of heterotrimeric Gαβγ proteins, followed by the recruitment of GPCR kinases and βarrestin (βarr) to initiate receptor desensitization and internal ... Full text Link to item Cite

Signal transduction at GPCRs: Allosteric activation of the ERK MAPK by β-arrestin.

Journal Article Proceedings of the National Academy of Sciences of the United States of America · October 2023 β-arrestins are multivalent adaptor proteins that bind active phosphorylated G protein-coupled receptors (GPCRs) to inhibit G protein signaling, mediate receptor internalization, and initiate alternative signaling events. β-arrestins link agonist-stimulate ... Full text Cite

Allosteric modulator potentiates β2AR agonist-promoted bronchoprotection in asthma models.

Journal Article J Clin Invest · September 15, 2023 Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote - with limited efficacy - bronchodilation in asthma. All β2-agonists are canonical orthosteric ligands ... Full text Link to item Cite

GPCR-mediated β-arrestin activation deconvoluted with single-molecule precision.

Journal Article Cell · May 12, 2022 β-arrestins bind G protein-coupled receptors to terminate G protein signaling and to facilitate other downstream signaling pathways. Using single-molecule fluorescence resonance energy transfer imaging, we show that β-arrestin is strongly autoinhibited in ... Full text Link to item Cite

β-Arrestin-Biased Allosteric Modulator Potentiates Carvedilol-Stimulated β Adrenergic Receptor Cardioprotection.

Journal Article Mol Pharmacol · December 2021 β 1 adrenergic receptors (β 1ARs) are central regulators of cardiac function and a drug target for cardiac disease. As a member of the G protein-coupled receptor family, β 1ARs activate cellular signaling by primarily coupling to Gs proteins to activate ad ... Full text Link to item Cite

The GPCR-β-arrestin complex allosterically activates C-Raf by binding its amino terminus.

Journal Article J Biol Chem · December 2021 G protein-coupled receptors (GPCRs) convert external stimuli into cellular signals through heterotrimeric guanine nucleotide-binding proteins (G-proteins) and β-arrestins (βarrs). In a βarr-dependent signaling pathway, βarrs link GPCRs to various downstrea ... Full text Link to item Cite

Unique Positive Cooperativity Between the β-Arrestin-Biased β-Blocker Carvedilol and a Small Molecule Positive Allosteric Modulator of the β2-Adrenergic Receptor.

Journal Article Mol Pharmacol · November 2021 Among β-blockers that are clinically prescribed for heart failure, carvedilol is a first-choice agent with unique pharmacological properties. Carvedilol is distinct from other β-blockers in its ability to elicit β-arrestin-biased agonism, which has been su ... Full text Link to item Cite

Noncanonical scaffolding of Gαi and β-arrestin by G protein-coupled receptors.

Journal Article Science · March 12, 2021 Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are common drug targets and canonically couple to specific Gα protein subtypes and β-arrestin adaptor proteins. G protein-mediated signaling and β-arrestin-mediated sig ... Full text Link to item Cite

DeSiphering receptor core-induced and ligand-dependent conformational changes in arrestin via genetic encoded trimethylsilyl 1H-NMR probe.

Journal Article Nat Commun · September 25, 2020 Characterization of the dynamic conformational changes in membrane protein signaling complexes by nuclear magnetic resonance (NMR) spectroscopy remains challenging. Here we report the site-specific incorporation of 4-trimethylsilyl phenylalanine (TMSiPhe) ... Full text Link to item Cite

Mechanism of β2AR regulation by an intracellular positive allosteric modulator.

Journal Article Science · June 28, 2019 Drugs targeting the orthosteric, primary binding site of G protein-coupled receptors are the most common therapeutics. Allosteric binding sites, elsewhere on the receptors, are less well-defined, and so less exploited clinically. We report the crystal stru ... Full text Link to item Cite

Small-Molecule Positive Allosteric Modulators of the β2-Adrenoceptor Isolated from DNA-Encoded Libraries.

Journal Article Mol Pharmacol · August 2018 Conventional drug discovery efforts at the β2-adrenoceptor (β2AR) have led to the development of ligands that bind almost exclusively to the receptor's hormone-binding orthosteric site. However, targeting the largely unexplored and evolutionarily unique al ... Full text Link to item Cite

Design, synthesis, and functional assessment of Cmpd-15 derivatives as negative allosteric modulators for the β2-adrenergic receptor.

Journal Article Bioorg Med Chem · May 15, 2018 The β2-adrenergic receptor (β2AR), a G protein-coupled receptor, is an important therapeutic target. We recently described Cmpd-15, the first small molecule negative allosteric modulator (NAM) for the β2AR. Herein we report in details the design, synthesis ... Full text Link to item Cite

Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility.

Journal Article Elife · February 2, 2018 Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and β-arrestin-1 are essential for fluid reabsorption because they mediate coupling between an orphan receptor ADGRG2 (GPR ... Full text Link to item Cite

Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure.

Journal Article Nature · August 24, 2017 G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ... Full text Link to item Cite

Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and β-Arrestin-1-Regulated Lactate Metabolism.

Journal Article Biol Psychiatry · April 15, 2017 BACKGROUND: Stress is a conserved physiological response in mammals. Whereas moderate stress strengthens memory to improve reactions to previously experienced difficult situations, too much stress is harmful. METHODS: We used specific β-adrenergic agonists ... Full text Link to item Cite

Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis.

Journal Article Proceedings of the National Academy of Sciences of the United States of America · March 2017 β-Arrestins (βarrs) interact with G protein-coupled receptors (GPCRs) to desensitize G protein signaling, to initiate signaling on their own, and to mediate receptor endocytosis. Prior structural studies have revealed two unique conformations of GPCR-βarr ... Full text Cite

Allosteric "beta-blocker" isolated from a DNA-encoded small molecule library.

Journal Article Proc Natl Acad Sci U S A · February 14, 2017 The β2-adrenergic receptor (β2AR) has been a model system for understanding regulatory mechanisms of G-protein-coupled receptor (GPCR) actions and plays a significant role in cardiovascular and pulmonary diseases. Because all known β-adrenergic receptor dr ... Full text Link to item Cite

Arrestin-biased AT1R agonism induces acute catecholamine secretion through TRPC3 coupling.

Journal Article Nat Commun · February 9, 2017 Acute hormone secretion triggered by G protein-coupled receptor (GPCR) activation underlies many fundamental physiological processes. GPCR signalling is negatively regulated by β-arrestins, adaptor molecules that also activate different intracellular signa ... Full text Link to item Cite

Conformationally selective RNA aptamers allosterically modulate the β2-adrenoceptor.

Journal Article Nat Chem Biol · September 2016 G-protein-coupled receptor (GPCR) ligands function by stabilizing multiple, functionally distinct receptor conformations. This property underlies the ability of 'biased agonists' to activate specific subsets of a given receptor's signaling profile. However ... Full text Link to item Cite

GPCR-G Protein-β-Arrestin Super-Complex Mediates Sustained G Protein Signaling.

Journal Article Cell · August 11, 2016 Classically, G protein-coupled receptor (GPCR) stimulation promotes G protein signaling at the plasma membrane, followed by rapid β-arrestin-mediated desensitization and receptor internalization into endosomes. However, it has been demonstrated that some G ... Full text Link to item Cite

Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation.

Journal Article Nature · July 21, 2016 G-protein-coupled receptors (GPCRs) modulate many physiological processes by transducing a variety of extracellular cues into intracellular responses. Ligand binding to an extracellular orthosteric pocket propagates conformational change to the receptor cy ... Full text Link to item Cite

Visualization of arrestin recruitment by a G-protein-coupled receptor.

Journal Article Nature · August 14, 2014 G-protein-coupled receptors (GPCRs) are critically regulated by β-arrestins, which not only desensitize G-protein signalling but also initiate a G-protein-independent wave of signalling. A recent surge of structural data on a number of GPCRs, including the ... Full text Open Access Link to item Cite

Monitoring protein conformational changes and dynamics using stable-isotope labeling and mass spectrometry.

Journal Article Nat Protoc · 2014 An understanding of the mechanism accompanying functional conformational changes associated with protein activation has important implications for drug design. Here we describe a powerful method, conformational changes and dynamics using stable-isotope lab ... Full text Link to item Cite

Discovery of β2 Adrenergic Receptor Ligands Using Biosensor Fragment Screening of Tagged Wild-Type Receptor.

Journal Article ACS Med Chem Lett · October 10, 2013 G-protein coupled receptors (GPCRs) are the primary target class of currently marketed drugs, accounting for about a quarter of all drug targets of approved medicines. However, almost all the screening efforts for novel ligand discovery rely exclusively on ... Full text Link to item Cite

Synthesis of β2-AR agonist BI-167107

Journal Article Chinese Journal of Organic Chemistry · March 1, 2013 BI-167107 is a new long-acting β2-adrenergic receptor (β2-AR) agonist, and has important application in determining the critical structures of receptor/ligand proteins complex of G-protein-coupled receptor (GPCR). By employing 2-nitroresorcinol as starting ... Full text Cite

Multiple ligand-specific conformations of the β2-adrenergic receptor.

Journal Article Nat Chem Biol · August 21, 2011 Seven-transmembrane receptors (7TMRs), also called G protein-coupled receptors (GPCRs), represent the largest class of drug targets, and they can signal through several distinct mechanisms including those mediated by G proteins and the multifunctional adap ... Full text Link to item Cite

Cucurbitacin I inhibits cell motility by indirectly interfering with actin dynamics.

Journal Article PLoS One · November 24, 2010 BACKGROUND: Cucurbitacins are plant natural products that inhibit activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway by an unknown mechanism. They are also known to cause changes in the organization o ... Full text Link to item Cite

G protein-coupled receptor kinase 2 activates radixin, regulating membrane protrusion and motility in epithelial cells.

Journal Article Biochim Biophys Acta · February 2010 Ezrin/radixin/moesin (ERM) proteins are membrane-cytoskeleton linkers that also have roles in signal transduction. Here we show that G protein-coupled receptor kinase 2 (GRK2) regulates membrane protrusion and cell migration during wound closure in Madin-D ... Full text Link to item Cite

Analogs of tetrahydroisoquinoline natural products that inhibit cell migration and target galectin-3 outside of its carbohydrate-binding site.

Journal Article J Biol Chem · September 5, 2008 Cell migration is central to a number of normal and disease processes. Small organic molecules that inhibit cell migration have potential as both research probes and therapeutic agents. We have identified two tetrahydroisoquinoline natural product analogs ... Full text Link to item Cite

Quinocarmycin analog DX-52-1 inhibits cell migration and targets radixin, disrupting interactions of radixin with actin and CD44.

Journal Article Chem Biol · September 2006 In the course of screening for new small-molecule modulators of cell motility, we discovered that quinocarmycin (also known as quinocarcin) analog DX-52-1 is an inhibitor of epithelial cell migration. While it has been assumed that the main target of DX-52 ... Full text Link to item Cite