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TitleStructural and signaling mechanisms of TAAR1 enabled preferential agonist design.
Journal, issue, pagesCell, Vol. 186, Issue 24, Page 5347-5362.e24, Year 2023
Publish dateNov 22, 2023
AuthorsPan Shang / Naikang Rong / Jing-Jing Jiang / Jie Cheng / Ming-Hui Zhang / Dongwei Kang / Lei Qi / Lulu Guo / Gong-Ming Yang / Qun Liu / Zhenzhen Zhou / Xiao-Bing Li / Kong-Kai Zhu / Qing-Biao Meng / Xiang Han / Wenqi Yan / Yalei Kong / Lejin Yang / Xiaohui Wang / Dapeng Lei / Xin Feng / Xinyong Liu / Xiao Yu / Yue Wang / Qian Li / Zhen-Hua Shao / Fan Yang / Jin-Peng Sun /
PubMed AbstractTrace 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 ...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 D 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.
External linksCell / PubMed:37963465
MethodsEM (single particle)
Resolution2.9 - 3.48 Å
Structure data

37429

8wc3

EMDB-37429, PDB-8wc3:
Cryo-EM structure of the SEP363856-bound mTAAR1-Gs complex
Method: EM (single particle) / Resolution: 3.0 Å

37430

8wc4

EMDB-37430, PDB-8wc4:
Cryo-EM structure of the ZH8651-bound mTAAR1-Gs complex
Method: EM (single particle) / Resolution: 3.1 Å

37431

8wc5

EMDB-37431, PDB-8wc5:
Cryo-EM structure of the TMA-bound mTAAR1-Gs complex
Method: EM (single particle) / Resolution: 3.3 Å

37432

8wc6

EMDB-37432, PDB-8wc6:
Cryo-EM structure of the PEA-bound mTAAR1-Gs complex
Method: EM (single particle) / Resolution: 3.2 Å

37433

8wc7

EMDB-37433, PDB-8wc7:
Cryo-EM structure of the ZH8667-bound mTAAR1-Gs complex
Method: EM (single particle) / Resolution: 3.1 Å

37434

8wc8

EMDB-37434, PDB-8wc8:
Cryo-EM structure of the ZH8651-bound hTAAR1-Gs complex
Method: EM (single particle) / Resolution: 2.9 Å

37435

8wc9

EMDB-37435, PDB-8wc9:
Cryo-EM structure of the ZH8651-bound mTAAR1-Gq complex
Method: EM (single particle) / Resolution: 3.2 Å

37436

8wca

EMDB-37436, PDB-8wca:
Cryo-EM structure of the PEA-bound hTAAR1-Gs complex
Method: EM (single particle) / Resolution: 3.48 Å

37437

8wcb

EMDB-37437, PDB-8wcb:
Cryo-EM structure of the CHA-bound mTAAR1-Gq complex
Method: EM (single particle) / Resolution: 3.1 Å

37438

8wcc

EMDB-37438, PDB-8wcc:
Cryo-EM structure of the CHA-bound mTAAR1 complex
Method: EM (single particle) / Resolution: 3.04 Å

Chemicals

ChemComp-UJL:
1-[(7~{S})-5,7-dihydro-4~{H}-thieno[2,3-c]pyran-7-yl]-~{N}-methyl-methanamine

ChemComp-VMT:
2-(4-bromophenyl)ethanamine

ChemComp-TMA:
TETRAMETHYLAMMONIUM ION / Tetramethylammonium

ChemComp-PEA:
2-PHENYLETHYLAMINE / alkaloid*YM / Phenethylamine

ChemComp-VMK:
2-[4-(3-fluorophenyl)phenyl]ethanamine

ChemComp-HAI:
CYCLOHEXYLAMMONIUM ION / Cyclohexylamine

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / SEP363856 / mTAAR1 / ZH8651 / Gq / TMA / PEA / ZH8667 / hTAAR1 / Gs / CHA

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