Biology subjects

Staus, D. P.

Publications and source records attributed to Staus, D. P..

4 recordsLinked to original sources

bioRxiv2026

Conformational Basis of Functionally Selective Allosteric Modulation of the Angiotensin II type 1 Receptor by Small Molecules

Blockade of signaling through the angiotensin II type 1 receptor (AT1R), a prototypical G protein-coupled receptor (GPCR), by angiotensin receptor blockers (ARBs) is a major therapeutic approach to treating a wide variety of cardiovascular and renal diseases1. Like most GPCRs, the AT1R signals through two transducers, G proteins and {beta}-arrestins2,3. Previous reports have described {beta}-arrestin-biased peptide orthosteric agonists for the AT1R with potential therapeutic advantages over currently available unbiased ARBs4-6. Here we report the DNA- encoded library screening-guided isolation and pharmacological characterization of the first small molecule AT1R allosteric ligands. We use cryo-electron microscopy, double electron- electron resonance spectroscopy, molecular dynamics simulations, and targeted mutagenesis to determine their binding sites, binding modes and conformational mechanisms driving their unique and divergent modulatory effects on G protein and {beta}-arrestin pathways. Our findings uncover new mechanisms for precisely controlling the dynamic behavior of the AT1R with implications for drug development targeting this pathophysiologically important receptor family.

biochemistry↗

bioRxiv2025

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

"Biased" ligands of the angiotensin II type 1 receptor (AT1R) preferentially activate G protein or {beta}-arrestin pathways by stabilizing distinct receptor conformations. Here we show that {beta}-arrestin-biased AT1R ligands further vary in their ability to stabilize different modes of {beta}-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 {beta}-arrestin core binding. Since the core and phosphosite interactions differentially activate the signaling, internalization, and desensitization functions of {beta}-arrestin, our data demonstrate that the allosteric effects of GPCR ligands could directly modulate {beta}-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.

biochemistry↗

bioRxiv2023

Antibodies Expand the Scope of Angiotensin Receptor Pharmacology

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.

pharmacology and toxicology↗

bioRxiv2019

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

G-protein-coupled receptors (GPCRs) enable cells to sense and respond appropriately to hormonal and environmental signals, and are a target of ~30% of all FDA-approved medications. Canonically, each GPCR couples to distinct G proteins, such as Gs, Gi, Gq or G12/13, as well as {beta}-arrestins. These transducer proteins translate and integrate extracellular stimuli sensed by GPCRs into intracellular signals through what are broadly considered separable signalling pathways. However, the ability of G proteins to directly interact with {beta}-arrestins to integrate signalling has not previously been appreciated. Here we show a novel interaction between Gi protein family members and {beta}-arrestin. Gi:{beta}-arrestin complexes were formed by all GPCRs tested, regardless of their canonical G protein isoform coupling, and could bind both GPCRs as well as the extracellular signal-regulated kinase (ERK). This novel paradigm of Gi:{beta}-arrestin scaffolds enhances our understanding of GPCR signalling.

cell biology↗