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Family C G-protein-coupled receptors (GPCRs) operate as obligate dimers with extracellular domains that recognize small ligands, leading to G-protein activation on the transmembrane (TM) domains of these receptors by an unknown mechanism 1 . Here we show structures of homodimers of the family C metabotropic glutamate receptor 2 (mGlu2) in distinct functional states and in complex with heterotrimeric G i . Upon activation of the extracellular domain, the two transmembrane domains undergo extensive rearrangement in relative orientation to establish an asymmetric TM6–TM6 interface that promotes conformational changes in the cytoplasmic domain of one protomer. Nucleotide-bound G i can be observed pre-coupled to inactive mGlu2, but its transition to the nucleotide-free form seems to depend on establishing the active-state TM6–TM6 interface. In contrast to family A and B GPCRs, G-protein coupling does not involve the cytoplasmic opening of TM6 but is facilitated through the coordination of intracellular loops 2 and 3, as well as a critical contribution from the C terminus of the receptor. The findings highlight the synergy of global and local conformational transitions to facilitate a new mode of G-protein activation. Cryo-electron microscopy structures show that metabotropic glutamate receptor 2 forms a dimer to which only one G protein is coupled, revealing the basis for asymmetric signal transduction.

The integration of bioreceptors with biocompatible substrates is crucial for advancing in vitro microphysiological systems used in disease modeling, drug screening, and biological research. Expanding spatial control over 3‐D bioreceptor patterning enables localized analyte detection, targeted molecular release, and selective sequestration. This study presents strategies for high‐resolution, multiplexed aptamer patterning within hydrogels, achieving the smallest 3‐D aptamer features reported to date (≈2 µm). Aptamers, synthetically engineered single‐stranded DNA or RNA, offer small size, high target specificity, and ease of chemical modification for covalent hydrogel integration. As a proof of concept, two DNA‐based aptamers targeting serotonin and dopamine were immobilized in a norbornene‐functionalized polyvinyl alcohol hydrogel. Systematic evaluation of UV photopatterning, digital light processing, and two‐photon polymerization enabled multiplexed, 3‐D aptamer patterns with micron‐scale resolution. This work establishes a framework for spatially resolved aptamer localization within 3‐D hydrogels, which is particularly important for biosensing in complex in vitro environments, where referencing specific binding requires precise positioning of control DNA near specific aptamers. These advances in spatially controlled aptamer functionalization open new possibilities for engineering modular biointerfaces. A hydrogel platform based on norbornene‐functionalized polyvinyl alcohol enables high‐resolution, 3‐D multiplexed patterning of DNA aptamers via two‐photon polymerization. Two distinct aptamers are covalently immobilized with single micron‐scale precision across the x, y, and z dimensions. This advancement in spatially controlled aptamer patterning opens new possibilities for engineering modular and tunable biointerfaces.