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	AAA+ ATPase p97/VCP mutants and inhibitor binding disrupt inter-domain coupling and subsequent allosteric activation.
ジャーナル・号・ページ	J Biol Chem, Vol. 297, Issue 4, Page 101187, Year 2021
掲載日	2021年9月11日
著者	Brian Caffrey / Xing Zhu / Alison Berezuk / Katharine Tuttle / Sagar Chittori / Sriram Subramaniam /
PubMed 要旨	The human AAA+ ATPase p97, also known as valosin-containing protein, a potential target for cancer therapeutics, plays a vital role in the clearing of misfolded proteins. p97 dysfunction is also ...The human AAA+ ATPase p97, also known as valosin-containing protein, a potential target for cancer therapeutics, plays a vital role in the clearing of misfolded proteins. p97 dysfunction is also known to play a crucial role in several neurodegenerative disorders, such as MultiSystem Proteinopathy 1 (MSP-1) and Familial Amyotrophic Lateral Sclerosis (ALS). However, the structural basis of its role in such diseases remains elusive. Here, we present cryo-EM structural analyses of four disease mutants p97, p97, p97, p97, as well as p97, implicated in resistance to the drug CB-5083, a potent p97 inhibitor. Our cryo-EM structures demonstrate that these mutations affect nucleotide-driven allosteric activation across the three principal p97 domains (N, D1, and D2) by predominantly interfering with either (1) the coupling between the D1 and N-terminal domains (p97 and p97), (2) the interprotomer interactions (p97), or (3) the coupling between D1 and D2 nucleotide domains (p97, p97). We also show that binding of the competitive inhibitor, CB-5083, to the D2 domain prevents conformational changes similar to those seen for mutations that affect coupling between the D1 and D2 domains. Our studies enable tracing of the path of allosteric activation across p97 and establish a common mechanistic link between active site inhibition and defects in allosteric activation by disease-causing mutations and have potential implications for the design of novel allosteric compounds that can modulate p97 function.
リンク	J Biol Chem / PubMed:34520757 / PubMed Central
手法	EM (単粒子)
解像度	3.0 - 3.8 Å
構造データ	24518 7rl6 EMDB-24518, PDB-7rl6: Cryo-EM structure of human p97-R155H mutant bound to ADP. 手法: EM (単粒子) / 解像度: 3.7 Å 24519 7rl7 EMDB-24519, PDB-7rl7: Cryo-EM structure of human p97-R155H mutant bound to ATPgS. 手法: EM (単粒子) / 解像度: 3.0 Å 24522 7rl9 EMDB-24522, PDB-7rl9: Cryo-EM structure of human p97-R191Q mutant bound to ADP. 手法: EM (単粒子) / 解像度: 3.3 Å 24523 7rla EMDB-24523, PDB-7rla: Cryo-EM structure of human p97-R191Q mutant bound to ATPgS. 手法: EM (単粒子) / 解像度: 3.1 Å 24524 7rlb EMDB-24524, PDB-7rlb: Cryo-EM structure of human p97-A232E mutant bound to ADP 手法: EM (単粒子) / 解像度: 3.3 Å 24525 7rlc EMDB-24525, PDB-7rlc: Cryo-EM structure of human p97-A232E mutant bound to ATPgS. 手法: EM (単粒子) / 解像度: 3.2 Å 24526 7rld EMDB-24526, PDB-7rld: Cryo-EM structure of human p97-E470D mutant bound to ADP. 手法: EM (単粒子) / 解像度: 3.4 Å 24528 7rlf EMDB-24528, PDB-7rlf: Cryo-EM structure of human p97-E470D mutant bound to ATPgS. 手法: EM (単粒子) / 解像度: 3.1 Å 24529 7rlg EMDB-24529, PDB-7rlg: Cryo-EM structure of human p97-D592N mutant bound to ADP. 手法: EM (単粒子) / 解像度: 3.7 Å 24530 7rlh EMDB-24530, PDB-7rlh: Cryo-EM structure of human p97-D592N mutant bound to ATPgS. 手法: EM (単粒子) / 解像度: 3.0 Å 24531 7rli EMDB-24531, PDB-7rli: Cryo-EM structure of human p97 bound to CB-5083 and ADP. 手法: EM (単粒子) / 解像度: 3.1 Å 24532 7rlj EMDB-24532, PDB-7rlj: Cryo-EM structure of human p97 bound to CB-5083 and ATPgS. 手法: EM (単粒子) / 解像度: 3.8 Å
化合物	ChemComp-ADP: ADENOSINE-5'-DIPHOSPHATE / ADP / ADP, エネルギー貯蔵分子YM / アデノシン二リン酸 ChemComp-AGS: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-γ-S / ATP-gamma-S, エネルギー貯蔵分子類似体YM ChemComp-MG: Unknown entry / マグネシウムジカチオン ChemComp-JDP: 1-[4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide / CB-5083
由来	homo sapiens (ヒト)
キーワード	HYDROLASE (加水分解酵素) / p97 / VCP / TERA / Inhibitor / CB-5083