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Here we describe the cryo-electron microscopy structure of the human histamine 2 receptor (H ₂ R) in an active conformation with bound histamine and in complex with G _s heterotrimeric protein at an overall resolution of 3.4 Å. The complex was generated by cotranslational insertion into preformed nanodisc membranes using cell-free synthesis in E. coli lysates. It is the first structure obtained by this detergent-free strategy and the first GPCR/G _s complex structure in lipid environment. Structural comparison with the inactive conformation of H ₂ R and the inactive and G _q -coupled active state of H ₁ R together with structure-guided functional experiments reveal molecular insights into the specificity of ligand binding and G protein coupling for this receptor family. We demonstrate lipid-modulated folding of cell-free synthesized H ₂ R, its agonist-dependent internalization and its interaction with endogenously synthesized H ₁ R and H ₂ R in HEK293 cells by applying a recently developed nanotransfer technique.