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BP: Fachverband Biologische Physik

BP 18: Focus session: Integrative Structural Modeling

BP 18.4: Hauptvortrag

Mittwoch, 11. März 2026, 11:45–12:15, BAR/0106

From Sparse Restraints to All-Atom Models: Integrative Reconstruction of Hidden GPCR Conformations — •Matthias Elgeti — Institute for Drug Discovery, Leipzig University Medical School, Leipzig, Germany

Transmembrane proteins such as G protein coupled receptors (GPCRs) play central roles in cellular signal transduction and constitute major targets for therapeutic intervention. Their intrinsic conformational flexibility, however, leads to the coexistence of multiple interconverting states, which complicates structural characterization by high-resolution methods. Site-directed spin labeling (SDSL) EPR spectroscopy is uniquely suited to probe such flexible systems independent of molecular size, but it provides only sparse structural restraints. To bridge this gap, we integrate SDSL-EPR distance data with deep-learning-based structure prediction and molecular dynamics simulations. Using the angiotensin receptor (AT1R), a key regulator of cardiovascular function, we demonstrate how this integrative approach reveals a ligand-stabilized conformational state with distinct functional properties. We further present a computational pipeline that reconstructs corresponding all-atom models from sparse spectroscopic restraints and enables systematic exploration of hidden conformational states, providing a general framework for structure-guided analysis of signaling mechanisms and future drug discovery.

Keywords: EPR spectroscopy; DEER; Deep learning; GPCR; Membrane proteins