EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Structural insights into vesicular monoamine storage and drug interactions.
ジャーナル・号・ページ	Nature, Vol. 629, Issue 8010, Page 235-243, Year 2024
掲載日	2024年3月18日
著者	Jin Ye / Huaping Chen / Kaituo Wang / Yi Wang / Aaron Ammerman / Samjhana Awasthi / Jinbin Xu / Bin Liu / Weikai Li /
PubMed 要旨	Biogenic monoamines-vital transmitters orchestrating neurological, endocrinal and immunological functions-are stored in secretory vesicles by vesicular monoamine transporters (VMATs) for controlled ...Biogenic monoamines-vital transmitters orchestrating neurological, endocrinal and immunological functions-are stored in secretory vesicles by vesicular monoamine transporters (VMATs) for controlled quantal release. Harnessing proton antiport, VMATs enrich monoamines around 10,000-fold and sequester neurotoxicants to protect neurons. VMATs are targeted by an arsenal of therapeutic drugs and imaging agents to treat and monitor neurodegenerative disorders, hypertension and drug addiction. However, the structural mechanisms underlying these actions remain unclear. Here we report eight cryo-electron microscopy structures of human VMAT1 in unbound form and in complex with four monoamines (dopamine, noradrenaline, serotonin and histamine), the Parkinsonism-inducing MPP, the psychostimulant amphetamine and the antihypertensive drug reserpine. Reserpine binding captures a cytoplasmic-open conformation, whereas the other structures show a lumenal-open conformation stabilized by extensive gating interactions. The favoured transition to this lumenal-open state contributes to monoamine accumulation, while protonation facilitates the cytoplasmic-open transition and concurrently prevents monoamine binding to avoid unintended depletion. Monoamines and neurotoxicants share a binding pocket that possesses polar sites for specificity and a wrist-and-fist shape for versatility. Variations in this pocket explain substrate preferences across the SLC18 family. Overall, these structural insights and supporting functional studies elucidate the mechanism of vesicular monoamine transport and provide the basis to develop therapeutics for neurodegenerative diseases and substance abuse.
リンク	Nature / PubMed:38499039 / PubMed Central
手法	EM (単粒子)
解像度	3.3 - 3.7 Å
構造データ	41235 8tgg EMDB-41235, PDB-8tgg: VMAT1 dimer with MPP+ and reserpine 手法: EM (単粒子) / 解像度: 3.6 Å 41236 8tgh EMDB-41236, PDB-8tgh: VMAT1 dimer with amphetamine and reserpine 手法: EM (単粒子) / 解像度: 3.5 Å 41237 8tgi EMDB-41237, PDB-8tgi: VMAT1 dimer with dopamine and reserpine 手法: EM (単粒子) / 解像度: 3.4 Å 41238 8tgj EMDB-41238, PDB-8tgj: VMAT1 dimer in unbound form and with reserpine 手法: EM (単粒子) / 解像度: 3.5 Å 41239 8tgk EMDB-41239, PDB-8tgk: VMAT1 dimer with histamine and reserpine 手法: EM (単粒子) / 解像度: 3.7 Å 41240 8tgl EMDB-41240, PDB-8tgl: VMAT1 dimer with norepinephrine and reserpine 手法: EM (単粒子) / 解像度: 3.4 Å 41241 8tgm EMDB-41241, PDB-8tgm: VMAT1 dimer with reserpine 手法: EM (単粒子) / 解像度: 3.5 Å 41242 8tgn EMDB-41242, PDB-8tgn: VMAT1 dimer with serotonin and reserpine 手法: EM (単粒子) / 解像度: 3.3 Å
化合物	ChemComp-WRF: 1-methyl-4-phenylpyridin-1-ium / MPP+ ChemComp-YHR: reserpine / レセルピン ChemComp-1WE: (2S)-1-phenylpropan-2-amine / d-アンフェタミン / デキストロアンフェタミン ChemComp-LDP: L-DOPAMINE / ド-パミン / 薬剤YM / Dopamine (medication) ChemComp-HSM: HISTAMINE / ヒスタミン / 神経伝達物質, ホルモンYM / ヒスタミン ChemComp-LNR: L-NOREPINEPHRINE / ノルアドレナリン / 神経伝達物質, ホルモンYM / ノルアドレナリン ChemComp-SRO: SEROTONIN / セロトニン / 神経伝達物質YM / セロトニン
由来	homo sapiens (ヒト)
キーワード	MEMBRANE PROTEIN (膜タンパク質) / VMAT / SLC18 / vascular monoamine transporter / monoamines / neurotransmitters / MPP+ / amphetamine / dopamine (ドーパミン) / reserpine / histamine (ヒスタミン) / norepinephrine (ノルアドレナリン) / serotonin (セロトニン)