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Talk by Meredith Skiba

Title: "Structural insights into angiotensin receptor modulation by diverse ligands"
Occasion: CRC - Seminar
Start: 26.09.2025, 12:00 Uhr
Location: CellNanOs, 38/201

About the speaker: Dr. Meredith Skiba conducts research at the Universität Michigan Medical School, Ann Arbor, Michigan, USA

G protein-coupled receptors (GPCRs) sample various conformational states to engage and activate downstream signaling pathways that regulate human physiology. Remarkedly, GPCRs are able to bind hundreds of distinct ligands, but share a conserved seven transmembrane core architecture and a relatively small set of signaling effectors. In some cases, binding of different ligands “biases” a receptor to engage with specific signaling effectors, inducing a subset of physiological responses. However, the molecular logic linking ligand recognition, receptor conformation, and downstream signaling outputs is still emerging.

We studied the conformational dynamics of the angiotensin II type I receptor (AT1R), a GPCR and important therapeutic target that regulates the cardiovascular and renal systems. AT1R inhibitors are commonly prescribed to treat high blood pressure but exhibit on-target fetotoxicity, restricting pharmacological treatments for hypertensive disorders during pregnancy, including preeclampsia, a leading cause of maternal and fetal death. We determined atomic level structures of AT1R bound to different activating ligands and found that the receptor adopts distinct active conformations to recruit signaling effectors that elicit differential physiological responses. We then characterized how chemically distinct antibody fragments (nanobodies) and small-molecule ligands employ different strategies to inactivate AT1R. Surprisingly, nanobodies stabilize the receptor in a previously unobserved conformational state that cannot engage signaling effectors, demonstrating that antibodies can modulate GPCR function in ways that are not readily achieved by conventional ligands. Further engineering of our antibody-based inhibitor has allowed us to selectively target maternal AT1R, which may address therapeutic gaps in maternal health left by the fetotoxicity of existing AT1R inhibitors.