Showing papers by "Robert J. Lefkowitz published in 2019"
TL;DR: A structural mechanism for biased ligand action at the angiotensin receptor that can be exploited to rationally design GPCR-targeting drugs with greater specificity of action is suggested.
168 citations
TL;DR: The crystal structure of active-state human AT1R bound to an AngII analog with partial agonist activity is determined and provides insight into how AngII and its analogs stimulate full or biased signaling, respectively.
130 citations
Duke University1, Columbia University2, Howard Hughes Medical Institute3, Rockefeller University4, City University of New York5, University of Michigan6, Stanford University7, Flanders Institute for Biotechnology8, VU University Amsterdam9, University of California, San Diego10, City College of New York11
TL;DR: The cryo-EM structure of a megaplex between chimeric GPCR, G protein and β-arrestin in their canonical active conformations provides insight into the basis of sustained G protein signaling upon megacomplex internalization.
Abstract: Classically, G-protein-coupled receptors (GPCRs) are thought to activate G protein from the plasma membrane and are subsequently desensitized by β-arrestin (β-arr). However, some GPCRs continue to signal through G protein from internalized compartments, mediated by a GPCR-G protein-β-arr 'megaplex'. Nevertheless, the molecular architecture of the megaplex remains unknown. Here, we present its cryo-electron microscopy structure, which shows simultaneous engagement of human G protein and bovine β-arr to the core and phosphorylated tail, respectively, of a single active human chimeric β2-adrenergic receptor with the C-terminal tail of the arginine vasopressin type 2 receptor (β2V2R). All three components adopt their canonical active conformations, suggesting that a single megaplex GPCR is capable of simultaneously activating G protein and β-arr. Our findings provide a structural basis for GPCR-mediated sustained internalized G protein signaling.
117 citations
TL;DR: Saving the Endangered Physician-ScientistPhysician-scientists have been a driving force in biomedical research and have made broad contributions in both the private and public sectors.
Abstract: Saving the Endangered Physician-Scientist Physician-scientists have been a driving force in biomedical research and have made broad contributions in both the private and public sectors. In the past...
98 citations
TL;DR: The crystal structure of the prototypic β 2 -adrenergic receptor in complex with an orthosteric agonist and compound-6FA, a positive allosteric modulator of this receptor is reported, revealing a pocket created by intracellular loop 2 and transmembrane segments 3 and 4, stabilizing the loop in an α-helical conformation required to engage the G protein.
Abstract: 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 structure of the prototypic β 2 -adrenergic receptor in complex with an orthosteric agonist and compound-6FA, a positive allosteric modulator of this receptor. It binds on the receptor’s inner surface in a pocket created by intracellular loop 2 and transmembrane segments 3 and 4, stabilizing the loop in an α-helical conformation required to engage the G protein. Structural comparison explains the selectivity of the compound for β 2 - over the β 1 -adrenergic receptor. Diversity in location, mechanism, and selectivity of allosteric ligands provides potential to expand the range of receptor drugs.
60 citations
TL;DR: This work interrogated the functional, pharmacological, and biophysical properties of a GPCR, the β2-adrenergic receptor (β2AR), in high-density lipoprotein (HDL) particles and linked these functional differences in detergent- and HDL-reconstituted β2AR to a change in the equilibrium between inactive and active receptor states.
33 citations
Patent•
08 Aug 2019TL;DR: In this article, a G-protein coupled receptor (GPCR) complex is described, which includes a non-native amino acid sequence located within the C-terminus of the GPCR and a synthetic phosphopeptide ligated to the sequence.
Abstract: The disclosure is directed to a G-protein coupled receptor complex. The complex includes (i) a chimeric G protein-coupled receptor (GPCR) comprising a non-native amino acid sequence located within the C-terminus of the GPCR and a synthetic phosphopeptide ligated to the non-native amino acid sequence; and (ii) a β-arrestin (βarr) protein bound to the C-terminus of the GPCR. The disclosure also provides an in vitro method for producing the aforementioned complex, as well as methods for identifying compounds or ligands which bind to and modulate the activity of the complex. Positive allosteric modulators of the β2 adrenergic receptor identified by screening a DNA-encoded library potentiate the activity of β2 agonists and have application in the treatment of obstructive airway disease, bronchospasm, or pre-term labor.