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	Targeting allostery in the Dynein motor domain with small molecule inhibitors.
ジャーナル・号・ページ	Cell Chem Biol, Vol. 28, Issue 10, Page 1460-1473.e15, Year 2021
掲載日	2021年10月21日
著者	Cristina C Santarossa / Keith J Mickolajczyk / Jonathan B Steinman / Linas Urnavicius / Nan Chen / Yasuhiro Hirata / Yoshiyuki Fukase / Nicolas Coudray / Damian C Ekiert / Gira Bhabha / Tarun M Kapoor /
PubMed 要旨	Cytoplasmic dyneins are AAA (ATPase associated with diverse cellular activities) motor proteins responsible for microtubule minus-end-directed intracellular transport. Dynein's unusually large size, ...Cytoplasmic dyneins are AAA (ATPase associated with diverse cellular activities) motor proteins responsible for microtubule minus-end-directed intracellular transport. Dynein's unusually large size, four distinct nucleotide-binding sites, and conformational dynamics pose challenges for the design of potent and selective chemical inhibitors. Here we use structural approaches to develop a model for the inhibition of a well-characterized S. cerevisiae dynein construct by pyrazolo-pyrimidinone-based compounds. These data, along with functional assays of dynein motility and mutagenesis studies, suggest that the compounds inhibit dynein by engaging the regulatory ATPase sites in the AAA3 and AAA4 domains, and not by interacting with dynein's main catalytic site in the AAA1 domain. A double Walker B mutation of the AAA3 and AAA4 sites substantially reduces enzyme activity, suggesting that targeting these regulatory domains is sufficient to inhibit dynein. Our findings reveal how chemical inhibitors can be designed to disrupt allosteric communication across dynein's AAA domains.
リンク	Cell Chem Biol / PubMed:34015309 / PubMed Central
手法	EM (単粒子) / X線回折
解像度	3.5 - 7.9 Å
構造データ	23838 7mi3 EMDB-23838: Signal subtracted reconstruction of AAA2, AAA3, and AAA4 domains of dynein in the presence of a pyrazolo-pyrimidinone-based compound, Map 4 PDB-7mi3: Signal subtracted reconstruction of AAA2, AAA3, and AAA4 domains of dynein in the presence of a pyrazolo-pyrimidinone-based compound, Model 4 手法: EM (単粒子) / 解像度: 3.5 Å 23841 7mi6 EMDB-23841: Yeast dynein motor domain in the presence of a pyrazolo-pyrimidinone-based compound, Map 1 PDB-7mi6: Yeast dynein motor domain in the presence of a pyrazolo-pyrimidinone-based compound, Model 1 手法: EM (単粒子) / 解像度: 3.9 Å 23842 7mi8 EMDB-23842: Signal subtracted reconstruction of AAA5 and AAA6 domains of dynein in the presence of a pyrazolo-pyrimidinone-based compound, Map 5 PDB-7mi8: Signal subtracted reconstruction of AAA5 and AAA6 domains of dynein in the presence of a pyrazolo-pyrimidinone-based compound, Model 5 手法: EM (単粒子) / 解像度: 3.7 Å EMDB-23844: Signal subtracted reconstruction of the AAA1 domain of dynein in the presence of a pyrazolo-pyrimidinone-based compound, Map 2 手法: EM (単粒子) / 解像度: 4.7 Å EMDB-23846: Signal subtracted reconstruction of the AAA1 domain of dynein in the presence of a pyrazolo-pyrimidinone-based compound, Map 3 手法: EM (単粒子) / 解像度: 7.9 Å PDB-7mi1: X-ray structure of yeast dynein motor domain in the presence of a pyrazolo-pyrimidinone-based compound (compound 20) 手法: X-RAY DIFFRACTION / 解像度: 4.5 Å
化合物	ChemComp-ZG7: (8S)-6-(3-bromophenoxy)-2-[1-(4-chlorophenyl)cyclopropyl]-7-hydroxypyrazolo[1,5-a]pyrimidine-3-carbonitrile ChemComp-ATP: ADENOSINE-5'-TRIPHOSPHATE / ATP / ATP, エネルギー貯蔵分子YM ChemComp-MG*: Unknown entry / マグネシウムジカチオン
由来	saccharomyces cerevisiae (パン酵母) enterobacteria phage t4 (ファージ)
キーワード	MOTOR PROTEIN / AAA ATPase / ATPase inhibitor