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-Structure paper
タイトル | Structural and signaling mechanisms of TAAR1 enabled preferential agonist design. |
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ジャーナル・号・ページ | Cell, Vol. 186, Issue 24, Page 5347-5362.e24, Year 2023 |
掲載日 | 2023年11月22日 |
著者 | Pan 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 要旨 | 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 ...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. |
リンク | Cell / PubMed:37963465 |
手法 | EM (単粒子) |
解像度 | 2.9 - 3.48 Å |
構造データ | EMDB-37429, PDB-8wc3: EMDB-37430, PDB-8wc4: EMDB-37431, PDB-8wc5: EMDB-37432, PDB-8wc6: EMDB-37433, PDB-8wc7: EMDB-37434, PDB-8wc8: EMDB-37435, PDB-8wc9: EMDB-37436, PDB-8wca: EMDB-37437, PDB-8wcb: EMDB-37438, PDB-8wcc: |
化合物 | ChemComp-UJL: ChemComp-VMT: ChemComp-TMA: ChemComp-PEA: ChemComp-VMK: ChemComp-HAI: |
由来 |
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キーワード | MEMBRANE PROTEIN / SEP363856 / mTAAR1 / ZH8651 / Gq / TMA / PEA / ZH8667 / hTAAR1 / Gs / CHA |