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 pharmacology of SV2A reveals an allosteric modulation mechanism in the major facilitator superfamily.
ジャーナル・号・ページ	Nat Commun, Vol. 16, Issue 1, Page 10748, Year 2025
掲載日	2025年11月28日
著者	Shabareesh Pidathala / Xiao Chen / Yaxin Dai / Long N Nguyen / Christoph Gorgulla / Yiming Niu / Fangyu Liu / Chia-Hsueh Lee /
PubMed 要旨	The synaptic vesicle glycoprotein 2A (SV2A), a member of the major facilitator superfamily (MFS), is a key target for antiseizure medications and a biomarker for synaptic density imaging. Despite its ...The synaptic vesicle glycoprotein 2A (SV2A), a member of the major facilitator superfamily (MFS), is a key target for antiseizure medications and a biomarker for synaptic density imaging. Despite its clinical importance, the mechanisms underlying SV2A ligand binding and modulation remain poorly understood. Here, we report sub-3 Å resolution cryo-electron microscopy (cryo-EM) structures of human SV2A in its apo form and in complex with FDA-approved antiseizure medication levetiracetam; PET imaging tracer UCB-J; experimental antiseizure drug padsevonil; and allosteric modulator UCB1244283. We find that levetiracetam and UCB-J induce vestibule occlusion, a hallmark conformational transition of MFS transporters that had not been observed in previous SV2A structures. UCB1244283 binds to an allosteric site and enhances orthosteric ligand engagement by stabilizing the occluded state and slowing ligand dissociation. Notably, padsevonil occupies both orthosteric and allosteric sites, functionally precluding modulation. These findings uncover an allosteric mechanism of regulation and provide a structural framework for the development of modulators targeting SV2A and related MFS transporters.
リンク	Nat Commun / PubMed:41315229 / PubMed Central
手法	EM (単粒子)
解像度	2.39 - 3.03 Å
構造データ	70562 9okf EMDB-70562, PDB-9okf: Cryo-EM structure of human SV2A in the apo state 手法: EM (単粒子) / 解像度: 2.8 Å 70563 9okg EMDB-70563, PDB-9okg: Cryo-EM structure of human SV2A in complex with levetiracetam 手法: EM (単粒子) / 解像度: 2.58 Å 70564 9okh EMDB-70564, PDB-9okh: Cryo-EM structure of human SV2A in complex with UCBJ 手法: EM (単粒子) / 解像度: 2.39 Å 70565 9oki EMDB-70565, PDB-9oki: Cryo-EM structure of human SV2A in complex with UCBJ and UCB1244283 手法: EM (単粒子) / 解像度: 2.67 Å 70566 9okj EMDB-70566, PDB-9okj: Cryo-EM structure of human SV2A in complex with padsevonil 手法: EM (単粒子) / 解像度: 2.68 Å 71812 9prs EMDB-71812, PDB-9prs: Cryo-EM structure of human SV2A in complex with Levetiracetam and UCB1244283 手法: EM (単粒子) / 解像度: 3.03 Å
化合物	化合物画像なし ChemComp-UKX: Unknown entry PDB-1cca: THE ASP-HIS-FE TRIAD OF CYTOCHROME C PEROXIDASE CONTROLS THE REDUCTION POTENTIAL, ELECTRONIC STRUCTURE, AND COUPLING OF THE TRYPTOPHAN FREE-RADICAL TO THE HEME PDB-1b1i: CRYSTAL STRUCTURE OF HUMAN ANGIOGENIN 化合物画像なし ChemComp-X3U: Unknown entry PDB-1b1j: CRYSTAL STRUCTURE OF HUMAN ANGIOGENIN VARIANT H13A.
由来	homo sapiens (ヒト)
キーワード	MEMBRANE PROTEIN / SLC transporter / SLC22 family / apo state / inhibitor / ligand binding