Dear Editor,rnThe G protein-coupled receptor GPR139 is involved in neuro-modulation,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 triggers4-7 several G protein pathways of which Gq/11 is the primary.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.6-9 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 inter-mediate 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).