7MI3

Signal subtracted reconstruction of AAA2, AAA3, and AAA4 domains of dynein in the presence of a pyrazolo-pyrimidinone-based compound, Model 4

7MI3 の概要

• エントリーDOI: 10.2210/pdb7mi3/pdb
• EMDBエントリー: 23838
• 分子名称: Fusion protein of Dynein and Endolysin, (8S)-6-(3-bromophenoxy)-2-[1-(4-chlorophenyl)cyclopropyl]-7-hydroxypyrazolo[1,5-a]pyrimidine-3-carbonitrile, ADENOSINE-5'-TRIPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: aaa atpase, atpase inhibitor, motor protein
• 由来する生物種: Saccharomyces cerevisiae (Baker's yeast); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 306384.82

構造登録者

Santarossa, C.C.,Coudray, N.,Urnavicius, L.,Ekiert, D.C.,Bhabha, G.,Kapoor, T.M. (登録日: 2021-04-16, 公開日: 2021-05-26, 最終更新日: 2024-05-29)

主引用文献

Santarossa, C.C.,Mickolajczyk, K.J.,Steinman, J.B.,Urnavicius, L.,Chen, N.,Hirata, Y.,Fukase, Y.,Coudray, N.,Ekiert, D.C.,Bhabha, G.,Kapoor, T.M.
Targeting allostery in the Dynein motor domain with small molecule inhibitors.
Cell Chem Biol, 28:1460-1473.e15, 2021

PubMed Abstract: 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.

PubMed: 34015309
DOI: 10.1016/j.chembiol.2021.04.024

実験手法

ELECTRON MICROSCOPY (3.5 Å)