+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8uvp | ||||||
---|---|---|---|---|---|---|---|
タイトル | Human p97/VCP R155H mutant structure with a triazole inhibitor (NSC819701/up) | ||||||
要素 | Transitional endoplasmic reticulum ATPase | ||||||
キーワード | MOTOR PROTEIN/INHIBITOR / AAA+ ATPase / p97 / VCP / triazole / allosteric inhibition / MOTOR PROTEIN-INHIBITOR complex | ||||||
機能・相同性 | 機能・相同性情報 positive regulation of Lys63-specific deubiquitinase activity / flavin adenine dinucleotide catabolic process / positive regulation of oxidative phosphorylation / VCP-NSFL1C complex / endosome to lysosome transport via multivesicular body sorting pathway / endoplasmic reticulum stress-induced pre-emptive quality control / cellular response to arsenite ion / Derlin-1 retrotranslocation complex / BAT3 complex binding / protein-DNA covalent cross-linking repair ...positive regulation of Lys63-specific deubiquitinase activity / flavin adenine dinucleotide catabolic process / positive regulation of oxidative phosphorylation / VCP-NSFL1C complex / endosome to lysosome transport via multivesicular body sorting pathway / endoplasmic reticulum stress-induced pre-emptive quality control / cellular response to arsenite ion / Derlin-1 retrotranslocation complex / BAT3 complex binding / protein-DNA covalent cross-linking repair / positive regulation of protein K63-linked deubiquitination / deubiquitinase activator activity / mitotic spindle disassembly / aggresome assembly / VCP-NPL4-UFD1 AAA ATPase complex / regulation of protein localization to chromatin / ubiquitin-modified protein reader activity / vesicle-fusing ATPase / NADH metabolic process / cellular response to misfolded protein / stress granule disassembly / positive regulation of mitochondrial membrane potential / negative regulation of protein localization to chromatin / K48-linked polyubiquitin modification-dependent protein binding / retrograde protein transport, ER to cytosol / regulation of aerobic respiration / positive regulation of ATP biosynthetic process / regulation of synapse organization / ATPase complex / ubiquitin-specific protease binding / ubiquitin-like protein ligase binding / MHC class I protein binding / autophagosome maturation / RHOH GTPase cycle / polyubiquitin modification-dependent protein binding / HSF1 activation / proteasomal protein catabolic process / endoplasmic reticulum to Golgi vesicle-mediated transport / translesion synthesis / Protein methylation / interstrand cross-link repair / ERAD pathway / ATP metabolic process / negative regulation of smoothened signaling pathway / endoplasmic reticulum unfolded protein response / Attachment and Entry / proteasome complex / viral genome replication / lipid droplet / Josephin domain DUBs / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / macroautophagy / Hh mutants are degraded by ERAD / Hedgehog ligand biogenesis / Defective CFTR causes cystic fibrosis / Translesion Synthesis by POLH / positive regulation of protein-containing complex assembly / establishment of protein localization / positive regulation of non-canonical NF-kappaB signal transduction / ABC-family proteins mediated transport / activation of cysteine-type endopeptidase activity involved in apoptotic process / ADP binding / autophagy / Aggrephagy / cytoplasmic stress granule / positive regulation of canonical Wnt signaling pathway / positive regulation of protein catabolic process / azurophil granule lumen / KEAP1-NFE2L2 pathway / double-strand break repair / Ovarian tumor domain proteases / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / E3 ubiquitin ligases ubiquitinate target proteins / Neddylation / site of double-strand break / cellular response to heat / protein phosphatase binding / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / secretory granule lumen / regulation of apoptotic process / ficolin-1-rich granule lumen / Attachment and Entry / protein ubiquitination / protein domain specific binding / DNA repair / intracellular membrane-bounded organelle / DNA damage response / ubiquitin protein ligase binding / lipid binding / glutamatergic synapse / endoplasmic reticulum membrane / Neutrophil degranulation / perinuclear region of cytoplasm / endoplasmic reticulum / ATP hydrolysis activity / protein-containing complex / RNA binding / extracellular exosome / extracellular region 類似検索 - 分子機能 | ||||||
生物種 | Homo sapiens (ヒト) | ||||||
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: 3.6 Å | ||||||
データ登録者 | Nandi, P. / DeVore, K. / Chiu, P.-L. | ||||||
資金援助 | 米国, 1件
| ||||||
引用 | ジャーナル: Commun Chem / 年: 2024 タイトル: Mechanism of allosteric inhibition of human p97/VCP ATPase and its disease mutant by triazole inhibitors. 著者: Purbasha Nandi / Kira DeVore / Feng Wang / Shan Li / Joel D Walker / Thanh Tung Truong / Matthew G LaPorte / Peter Wipf / Heidi Schlager / John McCleerey / William Paquette / Rod Carlo A ...著者: Purbasha Nandi / Kira DeVore / Feng Wang / Shan Li / Joel D Walker / Thanh Tung Truong / Matthew G LaPorte / Peter Wipf / Heidi Schlager / John McCleerey / William Paquette / Rod Carlo A Columbres / Taiping Gan / Yu-Ping Poh / Petra Fromme / Andrew J Flint / Mark Wolf / Donna M Huryn / Tsui-Fen Chou / Po-Lin Chiu / 要旨: Human p97 ATPase is crucial in various cellular processes, making it a target for inhibitors to treat cancers, neurological, and infectious diseases. Triazole allosteric p97 inhibitors have been ...Human p97 ATPase is crucial in various cellular processes, making it a target for inhibitors to treat cancers, neurological, and infectious diseases. Triazole allosteric p97 inhibitors have been demonstrated to match the efficacy of CB-5083, an ATP-competitive inhibitor, in cellular models. However, the mechanism is not well understood. This study systematically investigates the structures of new triazole inhibitors bound to both wild-type and disease mutant forms of p97 and measures their effects on function. These inhibitors bind at the interface of the D1 and D2 domains of each p97 subunit, shifting surrounding helices and altering the loop structures near the C-terminal α2 G helix to modulate domain-domain communications. A key structural moiety of the inhibitor affects the rotameric conformations of interacting side chains, indirectly modulating the N-terminal domain conformation in p97 R155H mutant. The differential effects of inhibitor binding to wild-type and mutant p97 provide insights into drug design with enhanced specificity, particularly for oncology applications. | ||||||
履歴 |
|
-構造の表示
構造ビューア | 分子: MolmilJmol/JSmol |
---|
-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 8uvp.cif.gz | 585.8 KB | 表示 | PDBx/mmCIF形式 |
---|---|---|---|---|
PDB形式 | pdb8uvp.ent.gz | 481.2 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8uvp.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/uv/8uvp ftp://data.pdbj.org/pub/pdb/validation_reports/uv/8uvp | HTTPS FTP |
---|
-関連構造データ
関連構造データ | 42626MC 8uv2C 8uvoC 8uvqC 9boqC 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 (文献) |
---|---|
類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-リンク
-集合体
登録構造単位 |
|
---|---|
1 |
|
-要素
#1: タンパク質 | 分子量: 89417.773 Da / 分子数: 6 / 変異: R155H / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: VCP / 発現宿主: Escherichia coli (大腸菌) / 参照: UniProt: P55072, vesicle-fusing ATPase #2: 化合物 | ChemComp-ADP / #3: 化合物 | ChemComp-XO8 / 分子量: 624.705 Da / 分子数: 6 / 由来タイプ: 合成 / 式: C30H34F2N8O3S / タイプ: SUBJECT OF INVESTIGATION 研究の焦点であるリガンドがあるか | Y | |
---|
-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
---|---|
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 |
-試料調製
構成要素 | 名称: p97/VCP AAA+ ATPase R155H mutant/NSC819701 / タイプ: COMPLEX 詳細: p97/VCP AAA+ ATPase R155H mutant bound with the triazole NSC819701. Entity ID: #1 / 由来: RECOMBINANT | |||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
分子量 | 値: 0.536 MDa / 実験値: NO | |||||||||||||||||||||||||
由来(天然) | 生物種: Homo sapiens (ヒト) | |||||||||||||||||||||||||
由来(組換発現) | 生物種: Escherichia coli (大腸菌) | |||||||||||||||||||||||||
緩衝液 | pH: 7.4 | |||||||||||||||||||||||||
緩衝液成分 |
| |||||||||||||||||||||||||
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | |||||||||||||||||||||||||
試料支持 | グリッドのタイプ: C-flat-2/1 | |||||||||||||||||||||||||
急速凍結 | 装置: FEI VITROBOT MARK IV / 凍結剤: ETHANE / 湿度: 90 % / 凍結前の試料温度: 298 K |
-電子顕微鏡撮影
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
---|---|
顕微鏡 | モデル: FEI TITAN KRIOS |
電子銃 | 電子線源: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELD / 倍率(公称値): 48077 X / 最大 デフォーカス(公称値): 2500 nm / 最小 デフォーカス(公称値): 800 nm / Cs: 2.7 mm / C2レンズ絞り径: 70 µm |
試料ホルダ | 凍結剤: NITROGEN 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER |
撮影 | 平均露光時間: 8 sec. / 電子線照射量: 47.84 e/Å2 / 検出モード: COUNTING フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) |
画像スキャン | サンプリングサイズ: 5 µm |
-解析
EMソフトウェア |
| ||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||
対称性 | 点対称性: C6 (6回回転対称) | ||||||||||||||||||||||||||||||||||||
3次元再構成 | 解像度: 3.6 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 31543 / アルゴリズム: BACK PROJECTION / クラス平均像の数: 1 / 対称性のタイプ: POINT | ||||||||||||||||||||||||||||||||||||
原子モデル構築 | プロトコル: RIGID BODY FIT / 空間: REAL | ||||||||||||||||||||||||||||||||||||
原子モデル構築 | PDB-ID: 5FTN Accession code: 5FTN / Source name: PDB / タイプ: experimental model | ||||||||||||||||||||||||||||||||||||
拘束条件 |
|