8zsv
From Proteopedia
Cryo-EM structure of the RO5263397-bound mTAAR1-Gs complex
Structural highlights
FunctionC562_ECOLX Electron-transport protein of unknown function.TAAR1_MOUSE Receptor for trace amines, including beta-phenylethylamine (b-PEA), p-tyramine (p-TYR), octopamine and tryptamine, with highest affinity for b-PEA and p-TYR. Unresponsive to classical biogenic amines, such as epinephrine and histamine and only partially activated by dopamine and serotonin. Trace amines are biogenic amines present in very low levels in mammalian tissues. Although some trace amines have clearly defined roles as neurotransmitters in invertebrates, the extent to which they function as true neurotransmitters in vertebrates has remained speculative. Trace amines are likely to be involved in a variety of physiological functions that have yet to be fully understood. The signal transduced by this receptor is mediated by the G(s)-class of G-proteins which activate adenylate cyclase.[1] Publication Abstract from PubMedIncreasing global concerns about psychoactive substance addiction and psychotic disorders highlight the need for comprehensive research into the structure-function relationship governing ligand recognition between these substances and their receptors in the brain. Recent studies indicate the significant involvement of trace amine-associated receptor 1 (TAAR1) in the signaling regulation of the hallucinogen lysergic acid diethylamide (LSD) and other antipsychotic drugs. This study presents structures of the TAAR1-Gs protein complex recognizing LSD, which exhibits a polypharmacological profile, and the partial agonist RO5263397, which is a drug candidate for schizophrenia and addiction. Moreover, we elucidate the cross-species recognition and partial activation mechanism for TAAR1, which holds promising implications from a drug discovery perspective. Through mutagenesis, functional studies, and molecular dynamics (MD) simulations, we provide a comprehensive understanding of a versatile TAAR1 pocket in recognizing various ligands as well as in the ligand-free state, underpinning the structural basis of its high adaptability. These findings offer valuable insights for the design of antipsychotic drugs. The versatile binding landscape of the TAAR1 pocket for LSD and other antipsychotic drug molecules.,Jiang K, Zheng Y, Zeng L, Wang L, Li F, Pu J, Lu Y, Zhao S, Xu F Cell Rep. 2024 Jul 11;43(7):114505. doi: 10.1016/j.celrep.2024.114505. PMID:39002128[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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