The G protein-coupled receptor GPR139 is involved in neuromodulation, and one of its agonists is in clinical trials for the treatment of cognitive impairment and negative symptoms of schizophrenia. While GPR139 is a understudied ‘orphan’ receptor, it can be activated by the amino acids L-Trp, L-Phe1 or α-Melanocyte-stimulating hormone (α-MSH) which is an endogenous agonist of melanocortin receptors.2,3 GPR139 activation triggers several G protein pathways of which Gq/11 is the primary.4,5,6,7 Of note, the expression of GPR139 correlates with that of the μ-opioid and dopamine D2 receptors in a broad range of the central nervous system (CNS), which acts as a regulator of μ-opioid and dopamine signaling.6,7,8,9 For example, GPR139 antagonist JNJ-3792165 increases the sensitivity of the μ-opioid receptor to morphine.6 Hitherto, the structural basis of how ligands interact with and activate GPR139 to transduce diverse signals has remained unknown. Furthermore, the more physiologically relevant intermediate states of GPCR–G protein complex structures in the nucleotide-bound forms are also elusive. Here, we report the cryo-electron microscopy (cryo-EM) structures of GPR139 in complex with a key reference ligand JNJ-63533054 which is an analog of agent TAK-04110 in clinical trial, and miniGs/q or Gi in nucleotide-free form, as well as the GPR139–JNJ-63533054–miniGs/q complex in GDP- and GTP-bound states, respectively (Fig. 1a–f).