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Analysis of the Structural Mechanism of ATP Inhibition at the AAA1 Subunit of Cytoplasmic Dynein-1 Using a Chemical “Toolkit”

School of Pharmacy, Memorial University of Newfoundland, 300 Prince Philip Dr, St. John’s, NL A1B 3V6, Canada
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Academic Editor: H.-Arno J. Müller
Int. J. Mol. Sci. 2021, 22(14), 7704; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147704
Received: 13 May 2021 / Revised: 11 July 2021 / Accepted: 14 July 2021 / Published: 19 July 2021
(This article belongs to the Section Biochemistry)
Dynein is a ~1.2 MDa cytoskeletal motor protein that carries organelles via retrograde transport in eukaryotic cells. The motor protein belongs to the ATPase family of proteins associated with diverse cellular activities and plays a critical role in transporting cargoes to the minus end of the microtubules. The motor domain of dynein possesses a hexameric head, where ATP hydrolysis occurs. The presented work analyzes the structure–activity relationship (SAR) of dynapyrazole A and B, as well as ciliobrevin A and D, in their various protonated states and their 46 analogues for their binding in the AAA1 subunit, the leading ATP hydrolytic site of the motor domain. This study exploits in silico methods to look at the analogues’ effects on the functionally essential subsites of the motor domain of dynein 1, since no similar experimental structural data are available. Ciliobrevin and its analogues bind to the ATP motifs of the AAA1, namely, the walker-A (W-A) or P-loop, the walker-B (W-B), and the sensor I and II. Ciliobrevin A shows a better binding affinity than its D analogue. Although the double bond in ciliobrevin A and D was expected to decrease the ligand potency, they show a better affinity to the AAA1 binding site than dynapyrazole A and B, lacking the bond. In addition, protonation of the nitrogen atom in ciliobrevin A and D, as well as dynapyrazole A and B, at the N9 site of ciliobrevin and the N7 of the latter increased their binding affinity. Exploring ciliobrevin A geometrical configuration suggests the E isomer has a superior binding profile over the Z due to binding at the critical ATP motifs. Utilizing the refined structure of the motor domain obtained through protein conformational search in this study exhibits that Arg1852 of the yeast cytoplasmic dynein could involve in the “glutamate switch” mechanism in cytoplasmic dynein 1 in lieu of the conserved Asn in AAA+ protein family. View Full-Text
Keywords: dynein motor domain; ATP hydrolysis; inhibition; ciliobrevin; dynapyrazole; analogues dynein motor domain; ATP hydrolysis; inhibition; ciliobrevin; dynapyrazole; analogues
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MDPI and ACS Style

Tati, S.; Alisaraie, L. Analysis of the Structural Mechanism of ATP Inhibition at the AAA1 Subunit of Cytoplasmic Dynein-1 Using a Chemical “Toolkit”. Int. J. Mol. Sci. 2021, 22, 7704. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147704

AMA Style

Tati S, Alisaraie L. Analysis of the Structural Mechanism of ATP Inhibition at the AAA1 Subunit of Cytoplasmic Dynein-1 Using a Chemical “Toolkit”. International Journal of Molecular Sciences. 2021; 22(14):7704. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147704

Chicago/Turabian Style

Tati, Sayi’Mone, and Laleh Alisaraie. 2021. "Analysis of the Structural Mechanism of ATP Inhibition at the AAA1 Subunit of Cytoplasmic Dynein-1 Using a Chemical “Toolkit”" International Journal of Molecular Sciences 22, no. 14: 7704. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147704

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