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Laura M. Wingler

Assistant Professor of Pharmacology and Cancer Biology
Pharmacology & Cancer Biology
C259 LSRC, Durham, NC 27710
Box 3813, Durham, NC 27710

Selected Publications


Antibodies expand the scope of angiotensin receptor pharmacology.

Journal Article Nat Chem Biol · May 14, 2024 G-protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small-molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often l ... Full text Link to item Cite

Nanobody-Mediated Dualsteric Engagement of the Angiotensin Receptor Broadens Biased Ligand Pharmacology.

Journal Article Mol Pharmacol · February 15, 2024 Dualsteric G protein-coupled receptor (GPCR) ligands are a class of bitopic ligands that consist of an orthosteric pharmacophore, which binds to the pocket occupied by the receptor's endogenous agonist, and an allosteric pharmacophore, which binds to a dis ... Full text Link to item Cite

Antibodies Expand the Scope of Angiotensin Receptor Pharmacology.

Journal Article bioRxiv · August 24, 2023 G protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often l ... Full text Link to item Cite

Molecular Determinants of Ligand-Induced Allosteric Coupling to Gq and Gi at the Angiotensin II Type 1 Receptor

Conference ASPET 2023 Annual Meeting Abstract - Cellular and Molecular Pharmacology · June 2023 Full text Cite

Nanobodies as Probes and Modulators of Cardiovascular G Protein-Coupled Receptors.

Journal Article J Cardiovasc Pharmacol · September 1, 2022 Understanding the activation of G protein-coupled receptors (GPCRs) is of paramount importance to the field of cardiovascular medicine due to the critical physiological roles of these receptors and their prominence as drug targets. Although many cardiovasc ... Full text Link to item Cite

Rapid generation of potent antibodies by autonomous hypermutation in yeast.

Journal Article Nat Chem Biol · October 2021 The predominant approach for antibody generation remains animal immunization, which can yield exceptionally selective and potent antibody clones owing to the powerful evolutionary process of somatic hypermutation. However, animal immunization is inherently ... Full text Link to item Cite

Rapid generation of potent antibodies by autonomous hypermutation in yeast.

Journal Article bioRxiv · November 11, 2020 The predominant approach for antibody generation remains animal immunization, which can yield exceptionally selective and potent antibody clones owing to the powerful evolutionary process of somatic hypermutation. However, animal immunization is inherently ... Full text Link to item Cite

Conformational Basis of G Protein-Coupled Receptor Signaling Versatility.

Journal Article Trends Cell Biol · September 2020 G protein-coupled receptors (GPCRs) are privileged structural scaffolds in biology that have the versatility to regulate diverse physiological processes. Interestingly, many GPCR ligands exhibit significant 'bias' - the ability to preferentially activate s ... Full text Link to item Cite

Synthetic nanobodies as angiotensin receptor blockers.

Journal Article Proc Natl Acad Sci U S A · August 18, 2020 There is considerable interest in developing antibodies as functional modulators of G protein-coupled receptor (GPCR) signaling for both therapeutic and research applications. However, there are few antibody ligands targeting GPCRs outside of the chemokine ... Full text Link to item Cite

So Long Llamas: Structure of Activated Angiotensin Receptor Stabilized by a Synthetic Nanobody

Conference The FASEB Journal · April 2020 Nanobodies are single‐domain antibody fragments that are derived from camelids and used extensively as research tools. Despite their usefulness, traditional immunization‐based approaches for generating nanobodies have proven ineffective for produci ... Full text Cite

Structure of the M2 muscarinic receptor-β-arrestin complex in a lipid nanodisc.

Journal Article Nature · March 2020 After activation by an agonist, G-protein-coupled receptors (GPCRs) recruit β-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes receptor endocytosis1. Additionally, β-arrestin directly regulates many cell signalling pathways tha ... Full text Link to item Cite

Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor.

Journal Article Science · February 21, 2020 Biased signaling, in which different ligands that bind to the same G protein-coupled receptor preferentially trigger distinct signaling pathways, holds great promise for the design of safer and more effective drugs. Its structural mechanism remains unclear ... Full text Link to item Cite

Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR.

Journal Article Science · February 21, 2020 Biased agonists of G protein-coupled receptors (GPCRs) preferentially activate a subset of downstream signaling pathways. In this work, we present crystal structures of angiotensin II type 1 receptor (AT1R) (2.7 to 2.9 angstroms) bound to three ligands wit ... Full text Link to item Cite

Detergent- and phospholipid-based reconstitution systems have differential effects on constitutive activity of G-protein-coupled receptors.

Journal Article J Biol Chem · September 6, 2019 A hallmark of G-protein-coupled receptors (GPCRs) is the conversion of external stimuli into specific cellular responses. In this tightly-regulated process, extracellular ligand binding by GPCRs promotes specific conformational changes within the seven tra ... Full text Link to item Cite

Distinctive Activation Mechanism for Angiotensin Receptor Revealed by a Synthetic Nanobody.

Journal Article Cell · January 24, 2019 The angiotensin II (AngII) type 1 receptor (AT1R) is a critical regulator of cardiovascular and renal function and is an important model for studies of G-protein-coupled receptor (GPCR) signaling. By stabilizing the receptor with a single-domain antibody f ... Full text Link to item Cite

Angiotensin Analogs with Divergent Bias Stabilize Distinct Receptor Conformations.

Journal Article Cell · January 24, 2019 "Biased" G protein-coupled receptor (GPCR) agonists preferentially activate pathways mediated by G proteins or β-arrestins. Here, we use double electron-electron resonance spectroscopy to probe the changes that ligands induce in the conformational distribu ... Full text Link to item Cite

G protein-coupled receptor kinases (GRKs) orchestrate biased agonism at the β2-adrenergic receptor.

Journal Article Sci Signal · August 21, 2018 Biased agonists of G protein-coupled receptors (GPCRs), which selectively activate either G protein- or β-arrestin-mediated signaling pathways, are of major therapeutic interest because they have the potential to show improved efficacy and specificity as d ... 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

Antibodies expand the scope of angiotensin receptor pharmacology.

Journal Article Nat Chem Biol · May 14, 2024 G-protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small-molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often l ... Full text Link to item Cite

Nanobody-Mediated Dualsteric Engagement of the Angiotensin Receptor Broadens Biased Ligand Pharmacology.

Journal Article Mol Pharmacol · February 15, 2024 Dualsteric G protein-coupled receptor (GPCR) ligands are a class of bitopic ligands that consist of an orthosteric pharmacophore, which binds to the pocket occupied by the receptor's endogenous agonist, and an allosteric pharmacophore, which binds to a dis ... Full text Link to item Cite

Antibodies Expand the Scope of Angiotensin Receptor Pharmacology.

Journal Article bioRxiv · August 24, 2023 G protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often l ... Full text Link to item Cite

Molecular Determinants of Ligand-Induced Allosteric Coupling to Gq and Gi at the Angiotensin II Type 1 Receptor

Conference ASPET 2023 Annual Meeting Abstract - Cellular and Molecular Pharmacology · June 2023 Full text Cite

Nanobodies as Probes and Modulators of Cardiovascular G Protein-Coupled Receptors.

Journal Article J Cardiovasc Pharmacol · September 1, 2022 Understanding the activation of G protein-coupled receptors (GPCRs) is of paramount importance to the field of cardiovascular medicine due to the critical physiological roles of these receptors and their prominence as drug targets. Although many cardiovasc ... Full text Link to item Cite

Rapid generation of potent antibodies by autonomous hypermutation in yeast.

Journal Article Nat Chem Biol · October 2021 The predominant approach for antibody generation remains animal immunization, which can yield exceptionally selective and potent antibody clones owing to the powerful evolutionary process of somatic hypermutation. However, animal immunization is inherently ... Full text Link to item Cite

Rapid generation of potent antibodies by autonomous hypermutation in yeast.

Journal Article bioRxiv · November 11, 2020 The predominant approach for antibody generation remains animal immunization, which can yield exceptionally selective and potent antibody clones owing to the powerful evolutionary process of somatic hypermutation. However, animal immunization is inherently ... Full text Link to item Cite

Conformational Basis of G Protein-Coupled Receptor Signaling Versatility.

Journal Article Trends Cell Biol · September 2020 G protein-coupled receptors (GPCRs) are privileged structural scaffolds in biology that have the versatility to regulate diverse physiological processes. Interestingly, many GPCR ligands exhibit significant 'bias' - the ability to preferentially activate s ... Full text Link to item Cite

Synthetic nanobodies as angiotensin receptor blockers.

Journal Article Proc Natl Acad Sci U S A · August 18, 2020 There is considerable interest in developing antibodies as functional modulators of G protein-coupled receptor (GPCR) signaling for both therapeutic and research applications. However, there are few antibody ligands targeting GPCRs outside of the chemokine ... Full text Link to item Cite

So Long Llamas: Structure of Activated Angiotensin Receptor Stabilized by a Synthetic Nanobody

Conference The FASEB Journal · April 2020 Nanobodies are single‐domain antibody fragments that are derived from camelids and used extensively as research tools. Despite their usefulness, traditional immunization‐based approaches for generating nanobodies have proven ineffective for produci ... Full text Cite

Structure of the M2 muscarinic receptor-β-arrestin complex in a lipid nanodisc.

Journal Article Nature · March 2020 After activation by an agonist, G-protein-coupled receptors (GPCRs) recruit β-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes receptor endocytosis1. Additionally, β-arrestin directly regulates many cell signalling pathways tha ... Full text Link to item Cite

Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor.

Journal Article Science · February 21, 2020 Biased signaling, in which different ligands that bind to the same G protein-coupled receptor preferentially trigger distinct signaling pathways, holds great promise for the design of safer and more effective drugs. Its structural mechanism remains unclear ... Full text Link to item Cite

Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR.

Journal Article Science · February 21, 2020 Biased agonists of G protein-coupled receptors (GPCRs) preferentially activate a subset of downstream signaling pathways. In this work, we present crystal structures of angiotensin II type 1 receptor (AT1R) (2.7 to 2.9 angstroms) bound to three ligands wit ... Full text Link to item Cite

Detergent- and phospholipid-based reconstitution systems have differential effects on constitutive activity of G-protein-coupled receptors.

Journal Article J Biol Chem · September 6, 2019 A hallmark of G-protein-coupled receptors (GPCRs) is the conversion of external stimuli into specific cellular responses. In this tightly-regulated process, extracellular ligand binding by GPCRs promotes specific conformational changes within the seven tra ... Full text Link to item Cite

Distinctive Activation Mechanism for Angiotensin Receptor Revealed by a Synthetic Nanobody.

Journal Article Cell · January 24, 2019 The angiotensin II (AngII) type 1 receptor (AT1R) is a critical regulator of cardiovascular and renal function and is an important model for studies of G-protein-coupled receptor (GPCR) signaling. By stabilizing the receptor with a single-domain antibody f ... Full text Link to item Cite

Angiotensin Analogs with Divergent Bias Stabilize Distinct Receptor Conformations.

Journal Article Cell · January 24, 2019 "Biased" G protein-coupled receptor (GPCR) agonists preferentially activate pathways mediated by G proteins or β-arrestins. Here, we use double electron-electron resonance spectroscopy to probe the changes that ligands induce in the conformational distribu ... Full text Link to item Cite

G protein-coupled receptor kinases (GRKs) orchestrate biased agonism at the β2-adrenergic receptor.

Journal Article Sci Signal · August 21, 2018 Biased agonists of G protein-coupled receptors (GPCRs), which selectively activate either G protein- or β-arrestin-mediated signaling pathways, are of major therapeutic interest because they have the potential to show improved efficacy and specificity as d ... 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

Sortase ligation enables homogeneous GPCR phosphorylation to reveal diversity in β-arrestin coupling.

Journal Article Proc Natl Acad Sci U S A · April 10, 2018 The ability of G protein-coupled receptors (GPCRs) to initiate complex cascades of cellular signaling is governed by the sequential coupling of three main transducer proteins, G protein, GPCR kinase (GRK), and β-arrestin. Mounting evidence indicates these ... Full text Link to item Cite

Multidimensional Tracking of GPCR Signaling via Peroxidase-Catalyzed Proximity Labeling.

Journal Article Cell · April 6, 2017 G-protein-coupled receptors (GPCRs) play critical roles in regulating physiological processes ranging from neurotransmission to cardiovascular function. Current methods for tracking GPCR signaling suffer from low throughput, modification or overexpression ... Full text Link to item 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

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

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

Regulation of β2-adrenergic receptor function by conformationally selective single-domain intrabodies.

Journal Article Mol Pharmacol · March 2014 The biologic activity induced by ligand binding to orthosteric or allosteric sites on a G protein-coupled receptor (GPCR) is mediated by stabilization of specific receptor conformations. In the case of the β2 adrenergic receptor, these ligands are generall ... Full text Link to item Cite

Transcriptional regulation improves the throughput of three-hybrid counter selections in Saccharomyces cerevisiae.

Journal Article Biotechnol J · December 2013 The yeast three-hybrid (Y3H) assay expands the fields of drug discovery and protein engineering by enabling the search of large variant libraries for targets that do not inherently produce a distinct, measurable phenotype. The Y3H assay links the DNA-bindi ... Full text Link to item Cite

Targeting β-arrestin2 Enhances Survival in a Murine Model of Chronic Myeloid Leukemia

Conference Blood · November 15, 2013 AbstractBackgroundChronic myeloid leukemia (CML) is a myeloproliferative neoplasm of hematopoietic stem cells characterized by presenc ... Full text 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

Gene assembly and combinatorial libraries in S. cerevisiae via reiterative recombination.

Journal Article Methods Mol Biol · 2013 While mutagenesis of single genes is now common practice in molecular biology, engineering multiple target genes still requires complex cloning techniques and thus is limited to expert laboratories. Here, we describe "Reiterative Recombination," a user-fri ... Full text Link to item Cite

Reiterative Recombination for the in vivo assembly of libraries of multigene pathways.

Journal Article Proc Natl Acad Sci U S A · September 13, 2011 The increasing sophistication of synthetic biology is creating a demand for robust, broadly accessible methodology for constructing multigene pathways inside of the cell. Due to the difficulty of rationally designing pathways that function as desired in vi ... Full text Link to item Cite