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Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D3.32 for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design. [Display omitted] • Activation profiles of m/hTAAR1 in response to a variety of EAM and pre-clinical drugs • Structures of m/hTAAR1-Gs/Gq in complex with EAMs, SEP, or synthetic compounds • Two pockets, PARP and SBP, enabled small EAM recognition and potent agonist design • Preferential Gq or Gs/Gq agonist of TAAR1 alleviated schizophrenia-like phenotypes Structural basis for the molecular recognition and signaling diversity of TAAR1 has been revealed, which facilitates structure-based preferential Gq or dual Gs/Gq pathway agonist design to alleviate MK-801-induced schizophrenia-like phenotypes. [ABSTRACT FROM AUTHOR]