How does ligand binding at the extracellular pocket of a GPCR reshape signaling on the intracellular side?

Biased agonism is often measured through pathway activation assays, but the structural origin of ligand bias remains difficult to trace. Can molecular simulations reveal the communication routes that link ligand binding to G protein or arrestin signaling?

In this conversation, computational biologist Anita Niveda explores how molecular dynamics and network analysis can map allosteric communication within GPCRs—revealing how microscopic structural pathways relate to macroscopic signaling outcomes.

From discovering bioinformatics as an undergraduate to developing computational methods for quantifying ligand bias, the discussion moves through the scientific thinking behind modeling receptor signaling, collaborations between academia and industry, and how computational tools are becoming predictive instruments in drug discovery.

Key Topics in This Episode

• How molecular dynamics simulations reveal communication pathways connecting ligand binding sites to G protein or arrestin interfaces

• Why mapping allosteric communication networks helps explain biased agonism in GPCR signaling

• What computational strategies can quantify ligand bias directly from receptor structures

• How receptor subtype selectivity emerges from subtle structural and dynamic differences in binding pockets

• Why academic–industry collaborations can accelerate method development in receptor pharmacology

• What career decisions shape the path from computational biology training to drug discovery roles

Timestamps

0:00 A structural question behind ligand bias
1:30 Introduction and scientific background
3:40 Discovering bioinformatics and computational biology
7:30 First encounters with GPCR structural biology
9:40 Finding and choosing a postdoctoral lab
16:40 Entering GPCR research and allosteric communication
18:20 Quantifying ligand bias using simulations
20:00 Mapping signaling pathways through receptor residues
23:30 Academic–industry collaboration with Boehringer Ingelheim
27:00 Moving from academia to industry research
35:00 Interviewing and transitioning into biotech
45:00 Aha moments in computational GPCR research
50:00 The diversity of GPCR families and signaling biology

Keywords: GPCR podcast, GPCR signaling, biased agonism, drug discovery, receptor pharmacology

Conserved neuropeptide Y GPCRs orchestrate both feeding and mating behaviors in mosquitoes, with direct translational parallels to human gut-brain signaling.

Quick Summary

Learn how receptor internalization and neuropeptide GPCR signaling underlie the regulation of mosquito host-seeking and reproduction. Dr. Laura Duvall details the use of CRISPR-based assay development and fluorescence-driven phenotyping to connect molecular manipulation to whole-animal behavior. Her approach provides actionable insights for gpcr drug discovery and tools to dissect homologous pathways across model systems, with implications for pharmacology research targeting vector-borne disease transmission.

Key Takeaways

• Neuropeptide Y GPCRs modulate both host attraction and mating in Aedes aegypti.

• CRISPR and fluorescence assays enable precise behavioral phenotyping in vivo.

• GPCR-targeted compounds designed for humans can modulate mosquito receptors.

• NPY receptor expression in mosquito gut mirrors mammalian gut-brain signaling axes.

• Automated behavioral assays combined with machine learning sharpen data resolution and reduce human bias.

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About the Guest

Dr. Laura Duvall earned her B.A. in Biochemistry and Biological Basis of Behavior from the University of Pennsylvania, followed by a PhD at Washington University in St. Louis, where she explored neuropeptide regulation of circadian behavior in Drosophila. Transitioning from fruit flies to mosquitoes, she pursued postdoctoral research at Rockefeller University with Leslie Vosshall, focusing on the molecular regulation of feeding and mating behaviors in Aedes aegypti. In 2019, she established her independent laboratory at Columbia University's Department of Biological Sciences and the Zuckerman Institute. Dr. Duvall’s work is recognized by awards including the Beckman Young Investigator Award, Klingenstein-Simons Fellowship in Neuroscience, and the Pew Scholars Program, reflecting her drive to unravel the complex signaling mechanisms that govern mosquito and broader animal behavior.

Guest on The Web

• LinkedIn: https://www.linkedin.com/in/laura-duvall-28a03485/

• Google Scholar: https://scholar.google.com/citations?user=Vk3KGSoAAAAJ&hl=en

• Lab: https://www.duvalllab.com/

Key Takeaways

How does the precise localization of GPCRs in lipid rafts reshape drug discovery strategy? Examine implications for functional assays and therapeutic innovation.

Explore the pivotal role of GPCR-lipid raft compartmentalization in receptor signaling, desensitization, and pharmacology research. Dr. Keyvan Sedaghat discusses assay approaches, regulatory mechanisms, and the translational impact of bitter taste receptors beyond sensory biology.

Leveraging decades of experience in assay development and database creation, he offers actionable insights for researchers optimizing GPCR drug discovery pipelines.

• Compartmentalization of GPCRs in lipid rafts directly influences receptor signaling and drug response.

• Desensitization pathways of dopamine D1 receptors depend on precise phosphorylation domains—challenging classical paradigms.

• Bitter taste receptors demonstrate functional relevance in non-gustatory tissues with emerging therapeutic applications.

• Database-driven research accelerates the identification of receptor-microdomain interactions for novel targets.

• Integration of computational modeling and biochemical validation is essential for advancing GPCR assay strategies.

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About the Guest

Dr. Keyvan Sedaghat holds a pharmacy degree and a PhD in cellular and molecular medicine, specializing in pharmacology, from the University of Ottawa. With over two decades of academic experience, he has served as a professor, senior lecturer, and chief scientific officer in the pharmaceutical and cosmetic industries. Dr. Sedaghat’s work spans peer-reviewed publications and editorial roles across journals in molecular pharmacology, cell signaling, and G protein-coupled receptors. His scientific drive centers on unraveling molecular mechanisms underlying GPCR function and translating those findings into effective teaching, research, and drug discovery strategies.

Guest on the Web:

• LinkedIn

• Google Scholar