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TitleTargeting allostery in the Dynein motor domain with small molecule inhibitors.
Journal, issue, pagesCell Chem Biol, Vol. 28, Issue 10, Page 1460-1473.e15, Year 2021
Publish dateOct 21, 2021
AuthorsCristina 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 AbstractCytoplasmic 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 linksCell Chem Biol / PubMed:34015309 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution3.5 - 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 molecule*YM / Adenosine triphosphate

ChemComp-MG:
Unknown entry

Source
  • saccharomyces cerevisiae (brewer's yeast)
  • enterobacteria phage t4 (virus)
KeywordsMOTOR PROTEIN / AAA ATPase / ATPase inhibitor

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