Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Targeting allostery in the Dynein motor domain with small molecule inhibitors.
Journal, issue, pages	Cell Chem Biol, Vol. 28, Issue 10, Page 1460-1473.e15, Year 2021
Publish date	Oct 21, 2021
Authors	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 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, ...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.
External links	Cell Chem Biol / PubMed:34015309 / PubMed Central
Methods	EM (single particle) / X-ray diffraction
Resolution	3.5 - 7.9 Å
Structure data	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 Method: EM (single particle) / Resolution: 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 Method: EM (single particle) / Resolution: 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 Method: EM (single particle) / Resolution: 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 Method: EM (single particle) / Resolution: 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 Method: EM (single particle) / Resolution: 7.9 Å PDB-7mi1: X-ray structure of yeast dynein motor domain in the presence of a pyrazolo-pyrimidinone-based compound (compound 20) Method: X-RAY DIFFRACTION / Resolution: 4.5 Å
Chemicals	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, energy-carrying moleculeYM ChemComp-MG*: Unknown entry
Source	saccharomyces cerevisiae (brewer's yeast) enterobacteria phage t4 (virus)
Keywords	MOTOR PROTEIN / AAA ATPase / ATPase inhibitor