7mi1

X-ray structure of yeast dynein motor domain in the presence of a pyrazolo-pyrimidinone-based compound (compound 20)

spinqualitylabelsall models 7mi1, resolution 4.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7mi1 is a 1 chain structure with sequence from Escherichia virus T4 and Saccharomyces cerevisiae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 4.5Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function D9IEF7_BPT4 DYHC_YEAST Cytoplasmic dynein acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP. Required to maintain uniform nuclear distribution in hyphae. May play an important role in the proper orientation of the mitotic spindle into the budding daughter cell yeast. Probably required for normal progression of the cell cycle. Publication Abstract from PubMed 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. Targeting allostery in the Dynein motor domain with small molecule inhibitors.,Santarossa CC, Mickolajczyk KJ, Steinman JB, Urnavicius L, Chen N, Hirata Y, Fukase Y, Coudray N, Ekiert DC, Bhabha G, Kapoor TM Cell Chem Biol. 2021 May 17. pii: S2451-9456(21)00217-8. doi:, 10.1016/j.chembiol.2021.04.024. PMID:34015309 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dynein 3D structures

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