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データを開く
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基本情報
登録情報 | データベース: PDB / ID: 8hk7 | ||||||
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タイトル | Structure of PKD2-F604P (Polycystin-2, TRPP2) with ML-SA1 | ||||||
![]() | Polycystin-2 | ||||||
![]() | MEMBRANE PROTEIN | ||||||
機能・相同性 | ![]() detection of nodal flow / metanephric smooth muscle tissue development / metanephric cortex development / metanephric cortical collecting duct development / metanephric distal tubule development / polycystin complex / mesonephric tubule development / mesonephric duct development / metanephric part of ureteric bud development / determination of liver left/right asymmetry ...detection of nodal flow / metanephric smooth muscle tissue development / metanephric cortex development / metanephric cortical collecting duct development / metanephric distal tubule development / polycystin complex / mesonephric tubule development / mesonephric duct development / metanephric part of ureteric bud development / determination of liver left/right asymmetry / renal tubule morphogenesis / metanephric ascending thin limb development / HLH domain binding / basal cortex / metanephric mesenchyme development / metanephric S-shaped body morphogenesis / renal artery morphogenesis / positive regulation of inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity / migrasome / cilium organization / VxPx cargo-targeting to cilium / centrosome duplication / detection of mechanical stimulus / calcium-induced calcium release activity / regulation of calcium ion import / cation channel complex / muscle alpha-actinin binding / placenta blood vessel development / voltage-gated monoatomic ion channel activity / cellular response to hydrostatic pressure / outward rectifier potassium channel activity / cellular response to fluid shear stress / voltage-gated monoatomic cation channel activity / cellular response to osmotic stress / non-motile cilium / actinin binding / motile cilium / transcription regulator inhibitor activity / determination of left/right symmetry / aorta development / inorganic cation transmembrane transport / neural tube development / ciliary membrane / voltage-gated sodium channel activity / protein heterotetramerization / embryonic placenta development / branching involved in ureteric bud morphogenesis / negative regulation of G1/S transition of mitotic cell cycle / spinal cord development / heart looping / negative regulation of ryanodine-sensitive calcium-release channel activity / voltage-gated potassium channel activity / cytoplasmic side of endoplasmic reticulum membrane / cell surface receptor signaling pathway via JAK-STAT / potassium channel activity / sodium ion transmembrane transport / voltage-gated calcium channel activity / monoatomic cation channel activity / basal plasma membrane / cellular response to cAMP / release of sequestered calcium ion into cytosol / potassium ion transmembrane transport / cytoskeletal protein binding / cellular response to calcium ion / ciliary basal body / liver development / establishment of localization in cell / lumenal side of endoplasmic reticulum membrane / phosphoprotein binding / calcium ion transmembrane transport / protein tetramerization / cellular response to reactive oxygen species / cytoplasmic vesicle membrane / cilium / mitotic spindle / Wnt signaling pathway / intracellular calcium ion homeostasis / calcium ion transport / positive regulation of nitric oxide biosynthetic process / cell-cell junction / lamellipodium / ATPase binding / heart development / regulation of cell population proliferation / positive regulation of cytosolic calcium ion concentration / basolateral plasma membrane / protein homotetramerization / transmembrane transporter binding / cell surface receptor signaling pathway / regulation of cell cycle / negative regulation of cell population proliferation / signaling receptor binding / calcium ion binding / endoplasmic reticulum membrane / positive regulation of gene expression / Golgi apparatus / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / protein homodimerization activity / extracellular exosome 類似検索 - 分子機能 | ||||||
生物種 | ![]() | ||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3 Å | ||||||
![]() | Chen, M.Y. / Su, Q. / Wang, Z.F. / Yu, Y. | ||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Molecular and structural basis of the dual regulation of the polycystin-2 ion channel by small-molecule ligands. 著者: Zhifei Wang / Mengying Chen / Qiang Su / Tiago D C Morais / Yan Wang / Elianna Nazginov / Akhilraj R Pillai / Feng Qian / Yigong Shi / Yong Yu / ![]() ![]() 要旨: Mutations in the gene, which encodes the polycystin-2 (PC2, also called TRPP2) protein, lead to autosomal dominant polycystic kidney disease (ADPKD). As a member of the transient receptor potential ...Mutations in the gene, which encodes the polycystin-2 (PC2, also called TRPP2) protein, lead to autosomal dominant polycystic kidney disease (ADPKD). As a member of the transient receptor potential (TRP) channel superfamily, PC2 functions as a non-selective cation channel. The activation and regulation of the PC2 channel are largely unknown, and direct binding of small-molecule ligands to this channel has not been reported. In this work, we found that most known small-molecule agonists of the mucolipin TRP (TRPML) channels inhibit the activity of the PC2_F604P, a gain-of-function mutant of the PC2 channel. However, two of them, ML-SA1 and SF-51, have dual regulatory effects, with low concentration further activating PC2_F604P, and high concentration leading to inactivation of the channel. With two cryo-electron microscopy (cryo-EM) structures, a molecular docking model, and mutagenesis results, we identified two distinct binding sites of ML-SA1 in PC2_F604P that are responsible for activation and inactivation, respectively. These results provide structural and functional insights into how ligands regulate PC2 channel function through unusual mechanisms and may help design compounds that are more efficient and specific in regulating the PC2 channel and potentially also for ADPKD treatment. | ||||||
履歴 |
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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ダウンロードとリンク
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ダウンロード
PDBx/mmCIF形式 | ![]() | 352.6 KB | 表示 | ![]() |
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PDB形式 | ![]() | 288.3 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
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-関連構造データ
関連構造データ | ![]() 34848MC ![]() 8k3sC M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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リンク
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集合体
登録構造単位 | ![]()
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要素
#1: タンパク質 | 分子量: 66029.828 Da / 分子数: 4 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() #2: 糖 | ChemComp-NAG / #3: 化合物 | ChemComp-CA / | #4: 化合物 | ChemComp-AQV / 研究の焦点であるリガンドがあるか | Y | |
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-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
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試料調製
構成要素 | 名称: Structure of PKD2-F604P (Polycystin-2, TRPP2) with ML-SA1 タイプ: COMPLEX / Entity ID: #1 / 由来: RECOMBINANT |
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由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() |
緩衝液 | pH: 7.5 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
急速凍結 | 凍結剤: ETHANE |
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電子顕微鏡撮影
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TITAN KRIOS |
電子銃 | 電子線源: ![]() |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2000 nm / 最小 デフォーカス(公称値): 1400 nm |
撮影 | 電子線照射量: 50 e/Å2 / フィルム・検出器のモデル: GATAN K3 (6k x 4k) |
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解析
CTF補正 | タイプ: NONE | ||||||||||||||||||||||||
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3次元再構成 | 解像度: 3 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 163172 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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