Unliganded Active State of the β2-Adrenergic Receptor Revealed by Pressure-Resolved DEER and ProGuide Molecular Modeling

Pressure-resolved DEER plus ProGuide modeling shows unliganded beta2-adrenergic receptor (β2AR) undergoes a pressure-dependent two-state equilibrium between inactive and active-like conformations.

• Why it matters: GPCRs signal through ensembles of transient conformations, but intermediate states are hard to detect with conventional structural methods.
• What they did: The authors combined pressure-resolved DEER with ProGuide biased molecular dynamics to map conformations of unliganded β2AR and compared them with β2AR bound to BI 167107.
• The result: They find allosteric coupling among transmembrane helices without ligand and that BI 167107-bound β2AR samples a smaller conformational space than the unliganded active conformation, supporting conformational selection.