About

Laura M. Wingler, Ph.D., is the Principal Investigator and an Assistant Professor of Pharmacology and Cancer Biology at Duke University. Her research focuses on pharmacology and cancer biology, as indicated by her role within the Duke University research team. She leads the Wingler Lab, which is dedicated to advancing understanding in these fields. Dr. Wingler is actively involved in mentoring graduate students and building her research team, including recruiting new members and postdoctoral researchers. Her work contributes to the broader scientific community through her leadership in pharmacology and cancer biology research at Duke University.

Research topics

• Chemistry
• Biology
• Biochemistry
• Cell biology
• Biophysics
• Computational biology
• Immunology
• Biotechnology
• Pharmacology
• Genetics
• Bioinformatics

Selected publications

• Angiotensin receptor conformations stabilized by biased ligands differentially modulate β-arrestin interactions

  Journal of Biological Chemistry · 2025-12-29

  articleOpen accessSenior author

  "Biased" ligands of the angiotensin II type 1 receptor (AT1R) preferentially activate G protein or β-arrestin pathways by stabilizing distinct receptor conformations. Here, we show that β-arrestin-biased AT1R ligands vary in their ability to stabilize different modes of β-arrestin interaction, specifically interactions with the AT1R seven-transmembrane core versus the phosphorylated C-terminus. By combining biochemical assays with double electron-electron resonance spectroscopy and integrative modeling, we show that ligands less effective at stabilizing the core complex promote an AT1R conformation with an intermediate transmembrane helix six position that is incompatible with β-arrestin core binding. Since interactions with the core and phosphosites of G protein-coupled receptors (GPCRs) differentially activate the signaling, internalization, and desensitization functions of β-arrestin, our data demonstrate that the allosteric effects of GPCR ligands could directly modulate β-arrestin activities. This "intra-transducer bias," or bias toward various functions of the same transducer, could enable finer control of GPCR drug pharmacology than previously thought possible.

  PublisherOA PDFDOI

• Angiotensin receptor conformations stabilized by biased ligands differentially modulate β-arrestin interactions

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-30

  preprintOpen accessSenior authorCorresponding

  Abstract “Biased” ligands of the angiotensin II type 1 receptor (AT1R) preferentially activate G protein or β-arrestin pathways by stabilizing distinct receptor conformations. Here we show that β-arrestin-biased AT1R ligands further vary in their ability to stabilize different modes of β-arrestin interaction, specifically interactions with the AT1R seven-transmembrane core versus the phosphorylated C-terminus. By combining biochemical assays with double electron-electron resonance (DEER) spectroscopy and integrative modeling, we show that ligands less effective at stabilizing the core complex promote an AT1R conformation with an intermediate transmembrane helix 6 position that is incompatible with β-arrestin core binding. Since the core and phosphosite interactions differentially activate the signaling, internalization, and desensitization functions of β-arrestin, our data demonstrate that the allosteric effects of GPCR ligands could directly modulate β-arrestin activities. This “intra-transducer bias,” or bias toward various functions of the same transducer, could enable finer control of GPCR drugs’ pharmacology than previously thought possible.

  PublisherOA PDFDOI

• Molecular imaging in experimental pulmonary fibrosis reveals that nintedanib unexpectedly modulates CCR2 immune cell infiltration

  EBioMedicine · 2024-11-07 · 14 citations

  articleOpen access

  BACKGROUND: Pulmonary fibrosis is a challenging clinical problem with lung pathology featuring immune cell infiltrates, fibroblast expansion, and matrix deposition. Molecular analysis of diseased lungs and preclinical models have uncovered C-C chemokine receptor type 2 (CCR2)+ monocyte egress from the bone marrow into the lung, where they acquire profibrotic activities. Current drug treatment is focused on fibroblast activity. Alternatively, therapeutic targeting and monitoring CCR2+ cells may be an effective patient management strategy. METHODS: Inhibition of CCR2+ cells and, as a benchmark, the clinical antifibrotic agent, nintedanib, were used in mouse lung fibrosis models. Lungs were evaluated directly for CCR2+ cell infiltration and by non-invasive CCR2+ positron emission tomography imaging (CCR2-PET). FINDINGS: Lung CCR2+ cells were significantly elevated in the bleomycin model as determined by tissue evaluation and CCR2-PET imaging. A protective treatment protocol with an oral CCR2 inhibitor was compared to oral nintedanib. While we expected disparate effects on CCR2+ cells, each drug similarly decreased lung CCR2+ cells and fibrosis. Chemotaxis assays showed nintedanib indirectly inhibited C-C motif chemokine 2 (CCL2)-mediated migration of CCR2+ cells. Even delayed therapeutic administration of nintedanib in bleomycin and the silicosis progressive fibrosis models decreased the accumulation of CCR2+ lung cells. In these treatments early CCR2-PET imaging predicted the later development of fibrosis. INTERPRETATION: The inhibition of CCR2+ cell egress is likely a critical controller for stabilising lung fibrosis, as provided by nintedanib. Imaging with CCR2-PET may be useful to monitor nintedanib treatment responses, guide decision-making in the treatment of patients with progressive pulmonary fibrosis, and as a biomarker for drug development. FUNDING: National Institutes of Health (NIH), R01HL131908 (SLB), R35HL145212 (YL), P41EB025815 (YL), K01DK133670 (DHK); Barnes Jewish Hospital Foundation (SLB).

  PublisherDOI

• Progress on the development of Class A GPCR‐biased ligands

  British Journal of Pharmacology · 2024-09-11 · 17 citations

  reviewOpen accessSenior author

  Class A G protein-coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numerous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, the adverse effects triggered by the available unbiased GPCR modulators, limit their use and therapeutic value. In this context, the elucidation of biased signalling has opened up new pharmacological avenues holding promise for safer therapeutics. Functionally selective ligands favour receptor conformations facilitating the recruitment of specific effectors and the modulation of the associated pathways. This review surveys the current drug discovery landscape of GPCR-biased modulators with a focus on recent advances. Understanding the biological effects of this preferential coupling is at different stages depending on the Class A GPCR family. Therefore, with a focus on individual GPCR families, we present a compilation of the functionally selective modulators reported over the past few years. In doing so, we dissect their therapeutic relevance, molecular determinants and potential clinical applications. LINKED ARTICLES: This article is part of a themed issue Complexity of GPCR Modulation and Signaling (ERNST). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.14/issuetoc.

  PublisherOA PDFDOI

• Phosphorylation patterns in the AT1R C-terminal tail specify distinct downstream signaling pathways

  Science Signaling · 2024-08-13 · 13 citations

  articleOpen access

  Different ligands stabilize specific conformations of the angiotensin II type 1 receptor (AT1R) that direct distinct signaling cascades mediated by heterotrimeric G proteins or β-arrestin. These different active conformations are thought to engage distinct intracellular transducers because of differential phosphorylation patterns in the receptor C-terminal tail (the "barcode" hypothesis). Here, we identified the AT1R barcodes for the endogenous agonist AngII, which stimulates both G protein activation and β-arrestin recruitment, and for a synthetic biased agonist that only stimulates β-arrestin recruitment. The endogenous and β-arrestin-biased agonists induced two different ensembles of phosphorylation sites along the C-terminal tail. The phosphorylation of eight serine and threonine residues in the proximal and middle portions of the tail was required for full β-arrestin functionality, whereas phosphorylation of the serine and threonine residues in the distal portion of the tail had little influence on β-arrestin function. Similarly, molecular dynamics simulations showed that the proximal and middle clusters of phosphorylated residues were critical for stable β-arrestin-receptor interactions. These findings demonstrate that ligands that stabilize different receptor conformations induce different phosphorylation clusters in the C-terminal tail as barcodes to evoke distinct receptor-transducer engagement, receptor trafficking, and signaling.

  PublisherOA PDFDOI

• Antibodies expand the scope of angiotensin receptor pharmacology

  Nature Chemical Biology · 2024-05-14 · 33 citations

  articleOpen access
  PublisherOA PDFDOI

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

  Journal of Pharmacology and Experimental Therapeutics · 2023-05-18

  articleOpen access
  PublisherOA PDFDOI

• Antibodies Expand the Scope of Angiotensin Receptor Pharmacology

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-08-24 · 4 citations

  preprintOpen access

  Abstract 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 limited at the receptor, tissue, and cellular level. Antibodies have the potential to address these limitations but their properties as GPCR ligands remain poorly characterized. Here, using protein engineering, pharmacological assays, and structural studies, we develop maternally selective heavy chain-only antibody (“nanobody”) antagonists against the angiotensin II type I receptor (AT1R) and uncover the unusual molecular basis of their receptor antagonism. We further show that our nanobodies can simultaneously bind to AT1R with specific small-molecule antagonists and demonstrate that ligand selectivity can be readily tuned. Our work illustrates that antibody fragments can exhibit rich and evolvable pharmacology, attesting to their potential as next-generation GPCR modulators.

  PublisherOA PDFDOI

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

  Molecular Pharmacology · 2023-12-21 · 13 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Rapid generation of potent antibodies by autonomous hypermutation in yeast

  Nature Chemical Biology · 2021 · 129 citations

  • Computational biology
  • Biology
  • Cell biology
  PublisherOA PDFDOI

Frequent coauthors

• Robert J. Lefkowitz

  192 shared

• Dean P. Staus

  Duke Medical Center

  177 shared

• Seungkirl Ahn

  Duke University Hospital

  87 shared

• Ryan T. Strachan

  57 shared

• Brian K. Kobilka

  Stanford University

  55 shared

• Els Pardon

  Vrije Universiteit Brussel

  52 shared

• Jan Steyaert

  Vrije Universiteit Brussel

  52 shared

• Søren G. F. Rasmussen

  University of Copenhagen

  49 shared

Labs

• The Wingler Lab at Duke UniversityPI

Education

• B.S., Biochemistry

  North Carolina State University

• B.S., Chemistry

  North Carolina State University

• Ph.D., Chemistry

  Columbia University