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	PIP2 Binding at Allosteric Site Blocks Activation in Human Rod CNG Channels.
ジャーナル・号・ページ	bioRxiv, Year 2025
掲載日	2025年12月21日
著者	Taehyun Park / Crina M Nimigean /
PubMed 要旨	Phosphatidylinositol-4,5-bisphosphate (PIP2) is a ubiquitous signaling lipid that regulates multiple ion channels. In human cyclic nucleotide-gated (CNG) channels, including the rod photoreceptor ...Phosphatidylinositol-4,5-bisphosphate (PIP2) is a ubiquitous signaling lipid that regulates multiple ion channels. In human cyclic nucleotide-gated (CNG) channels, including the rod photoreceptor channel, PIP2 has been reported to exert inhibitory effects, but the underlying mechanism has remained unclear. Because this inhibition lowers the apparent cGMP sensitivity of rod CNG channels, it can play a key role in controlling the light sensitivity and dynamic range of rod photoreceptors. Here we report how PIP2 modulates the function of human CNGA1 channels, the major subunit of human rod photoreceptor CNG channels. Ensemble ion flux assays with liposome-reconstituted purified CNGA1 channels demonstrated robust inhibition by PIP2 via a reduction in apparent cGMP sensitivity, and single-channel recordings revealed PIP2 reduces the channel's open probability without altering unitary conductance. To uncover the structural basis, we determined cryo-EM structures of CNGA1 in lipid nanodiscs under multiple ligand conditions. In PIP2-free conditions, closed, intermediate, and open conformations were observed, whereas in the presence of PIP2, the open state was absent. Density consistent with bound PIP2 was detected at inter-protomer grooves between the voltage-sensing and pore domains indicating that PIP2 binding stabilizes non-conductive conformations by sterically preventing C-linker elevation and outward movement of helix S6, conformational changes needed for pore dilation. Collectively, our results establish a structural mechanism for PIP2-mediated inhibition of rod CNG channels, define a mechanistic framework for phosphoinositide control of ligand-gated channels across the CNG superfamily, and provide an inhibitory allosteric binding site for future drug targeting in this channel family.
リンク	bioRxiv / PubMed:41473327 / PubMed Central
手法	EM (単粒子)
解像度	2.07 - 2.64 Å
構造データ	74534 9zpv EMDB-74534, PDB-9zpv: CNGA1 channel closed state in nanodisc cGMP-free 手法: EM (単粒子) / 解像度: 2.07 Å 74535 9zpw EMDB-74535, PDB-9zpw: CNGA1 channel intermediate state in nanodisc cGMP-bound 手法: EM (単粒子) / 解像度: 2.47 Å 74536 9zpx EMDB-74536, PDB-9zpx: CNGA1 channel open state in nanodisc cGMP-bound 手法: EM (単粒子) / 解像度: 2.64 Å 74537 9zpy EMDB-74537, PDB-9zpy: CNGA1 channel closed state in nanodisc with brain PIP2 cGMP-free 手法: EM (単粒子) / 解像度: 2.48 Å 74538 9zpz EMDB-74538, PDB-9zpz: CNGA1 channel intermediate state in nanodisc with brain PIP2 cGMP-bound 手法: EM (単粒子) / 解像度: 2.64 Å 74539 9zq0 EMDB-74539, PDB-9zq0: CNGA1 channel closed state in nanodisc with diC8-PIP2 cGMP-free 手法: EM (単粒子) / 解像度: 2.11 Å 74540 9zq1 EMDB-74540, PDB-9zq1: CNGA1 channel intermediate state in nanodisc with diC8-PIP2 cGMP-bound 手法: EM (単粒子) / 解像度: 2.22 Å
化合物	ChemComp-CLR: CHOLESTEROL / コレステロ-ル ChemComp-PCW: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC / DOPC, リン脂質YM ChemComp-K: Unknown entry / カリウムカチオン ChemComp-PCG: CYCLIC GUANOSINE MONOPHOSPHATE / cGMP ChemComp-PT5: [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho / リン脂質YM ChemComp-PIO: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate / 1-O-(1-O,2-O-ジオクタノイル-L-グリセロ-3-ホスホ)-D-myo-イノシト-ル4,5-ビスりん酸
由来	homo sapiens (ヒト)
キーワード	TRANSPORT PROTEIN / Cyclic nucleotide-gated channel / Rod photoreceptor / CNGA1 / Ion channel