8ZSV

Cryo-EM structure of the RO5263397-bound mTAAR1-Gs complex

This is a non-PDB format compatible entry.

Summary for 8ZSV

• Entry DOI: 10.2210/pdb8zsv/pdb
• EMDB information: 60427
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, taar1, cryo-em, membrane protein/immune system, membrane protein-immune system complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 144773.91

Authors

Jiang, K.X.,Zheng, Y.,Xu, F. (deposition date: 2024-06-05, release date: 2024-07-24, Last modification date: 2024-10-23)

Primary citation

Jiang, K.,Zheng, Y.,Zeng, L.,Wang, L.,Li, F.,Pu, J.,Lu, Y.,Zhao, S.,Xu, F.
The versatile binding landscape of the TAAR1 pocket for LSD and other antipsychotic drug molecules.
Cell Rep, 43:114505-114505, 2024

PubMed Abstract: Increasing 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.

PubMed: 39002128
DOI: 10.1016/j.celrep.2024.114505

Experimental method

ELECTRON MICROSCOPY (2.96 Å)