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-Structure paper
タイトル | Targeting allostery in the Dynein motor domain with small molecule inhibitors. |
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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 | EMDB-23838: Signal subtracted reconstruction of AAA2, AAA3, and AAA4 domains of dynein in the presence of a pyrazolo-pyrimidinone-based compound, Map 4 EMDB-23841: Yeast dynein motor domain in the presence of a pyrazolo-pyrimidinone-based compound, Map 1 EMDB-23842: Signal subtracted reconstruction of AAA5 and AAA6 domains of dynein in the presence of a pyrazolo-pyrimidinone-based compound, Map 5 EMDB-23844: EMDB-23846: PDB-7mi1: |
化合物 | ChemComp-ZG7: ChemComp-ATP: ChemComp-MG: |
由来 |
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キーワード | MOTOR PROTEIN / AAA ATPase / ATPase inhibitor |