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	TRPML2 in distinct states reveals the activation and modulation principles of the TRPML family.
ジャーナル・号・ページ	Nat Commun, Vol. 16, Issue 1, Page 5325, Year 2025
掲載日	2025年6月17日
著者	Philip Schmiege / Dawid Jaślan / Michael Fine / Nidish Ponath Sadanandan / Alexandra Hatton / Nadia Elghobashi-Meinhardt / Christian Grimm / Xiaochun Li /
PubMed 要旨	TRPML2 activity is critical for endolysosomal integrity and chemokine secretion, and can be modulated by various ligands. Interestingly, two ML-SI3 isomers regulate TRPML2 oppositely. The molecular ...TRPML2 activity is critical for endolysosomal integrity and chemokine secretion, and can be modulated by various ligands. Interestingly, two ML-SI3 isomers regulate TRPML2 oppositely. The molecular mechanism underlying this unique isomeric preference as well as the TRPML2 agonistic mechanism remains unknown. Here, we present six cryo-EM structures of human TRPML2 in distinct states revealing that the π-bulge of the S6 undergoes a π-α transition upon agonist binding, highlighting the remarkable role of the π-bulge in ion channel regulation. Moreover, we identify that PI(3,5)P allosterically affects the pose of ML2-SA1, a TRPML2 specific activator, resulting in an open channel without the π-α transition. Functional and structural studies show that mutating the S5 of TRPML1 to that of TRPML2 enables the mutated TRPML1 to be activated by (+)ML-SI3 and ML2-SA1. Thus, our work elucidates the activation mechanism of TRPML channels and paves the way for the development of selective TRPML modulators.
リンク	Nat Commun / PubMed:40527873 / PubMed Central
手法	EM (単粒子)
解像度	2.35 - 3.01 Å
構造データ	48135 9eks EMDB-48135, PDB-9eks: ML2-SA1 bound TRPML1-V432A/A433G in a partially open state 手法: EM (単粒子) / 解像度: 2.42 Å 48136 9ekt EMDB-48136, PDB-9ekt: (+)ML-SI3 bound TRPML1-V432A/A433G in a partially open state 手法: EM (単粒子) / 解像度: 2.35 Å 48137 9eku EMDB-48137, PDB-9eku: (+)ML-SI3 bound TRPML1-V432A/A433G in a pre-open state 手法: EM (単粒子) / 解像度: 2.68 Å 48138 9ekv EMDB-48138, PDB-9ekv: ML-SA5 bound TRPML1 in an open state 手法: EM (単粒子) / 解像度: 2.75 Å 48139 9ekw EMDB-48139, PDB-9ekw: Apo TRPML2 in a closed state 手法: EM (単粒子) / 解像度: 3.01 Å 48140 9ekx EMDB-48140, PDB-9ekx: (-)ML-SI3 bound TRPML2 in a closed state 手法: EM (単粒子) / 解像度: 2.6 Å 48141 9eky EMDB-48141, PDB-9eky: (+)ML-SI3 bound TRPML2 in a pre-open state 手法: EM (単粒子) / 解像度: 2.67 Å 48142 9ekz EMDB-48142, PDB-9ekz: (+)ML-SI3 bound TRPML2 in an open state 手法: EM (単粒子) / 解像度: 2.61 Å 48143 9el0 EMDB-48143, PDB-9el0: ML2-SA1 bound TRPML2 in a pre-open state 手法: EM (単粒子) / 解像度: 2.45 Å 48144 9el1 EMDB-48144, PDB-9el1: ML2-SA1/PI(3,5)P2 bound TRPML2 in an open state 手法: EM (単粒子) / 解像度: 2.61 Å
化合物	PDB-1bi6: NMR STRUCTURE OF BROMELAIN INHIBITOR VI FROM PINEAPPLE STEM ChemComp-ZB4: N-{(1S,2S)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl}benzenesulfonamide / チャネルブロッカー, アンタゴニストYM PDB-1ivc: STRUCTURES OF AROMATIC INHIBITORS OF INFLUENZA VIRUS NEURAMINIDASE PDB-1iv3: Structure of 2C-Methyl-D-erythritol-2,4-cyclodiphosphate Synthase (bound form MG atoms) ChemComp-EUJ*: (2R)-3-{[(S)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,4,6-trihydroxy-3,5-bis(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctanoate
由来	homo sapiens (ヒト)
キーワード	TRANSPORT PROTEIN / TRPML / calcium channel / ion transport / cryo-EM / MEMBRANE PROTEIN