G protein-coupled receptors (GPCRs) are the largest class of cell surface drug targets. Advances in stabilization of GPCR:transducer complexes, together with improvements in cryoelectron microscopy (cryo-EM) have recently been applied to structure-assisted drug design for GPCR agonists. Nonetheless, limitations in the commercial application of these approaches, including the use of nanobody 35 (Nb35) to aid complex stabilization and the high cost of 300 kV imaging, have restricted broad application of cryo-EM in drug discovery. Here, using the PF 06882961-bound GLP-1R as exemplar, we validated the formation of stable complexes with a modified Gs protein in the absence of Nb35. In parallel, we compare 200 versus 300 kV image acquisition using a Falcon 4 or K3 direct electron detector. Moreover, the 200 kV Glacios-Falcon 4 yielded a 3.2 Å map with clear density for bound drug and multiple structurally ordered waters. Our work paves the way for broader commercial application of cryo-EM for GPCR drug discovery. Display omitted •High-resolution imaging of GPCRs using non-proprietary technologies•3.2 Å structure of a GPCR using a 200 kV microscope•Imaging of small-molecule agonist class B GPCR with no stabilizing nanobodies Traditionally, G protein-coupled receptors (GPCRs) need to be biochemically stabilized to be studied by cryo-EM. We show that it is possible to obtain high-quality 3D reconstructions without the need for a stabilizing nanobody. We also show that excellent imaging results can be obtained on both 200 and 300 kV microscopes.