Targeting Allostery in the Dynein Motor Domain with Small Molecule Inhibitors

Santarossa, Cristina; Mickolajczyk, Keith J.; Steinman, Jonathan B.; Urnavicius, L.; Chen, Nan; Hirata, Yasuhiko; Fukase, Yoshiyuki; Coudray, Nicolas; Ekiert, D.C.; Bhabha, Gira; Kapoor, Tarun M.

doi:10.1101/2020.09.22.308700

Cited by 3 publications

(2 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…New analogs of dynapyrazole, recently introduced by Santarossa et al, [36] have shown to be potent in inhibiting basal ATPase activity of dynein while binding to AAA3 and AAA4. The binding assessment of analogs 3-48 will be critical in evaluating their inhibitory mode of action at the AAA3 binding site, which is not conserved in axonemal dynein and cytoplasmic dynein 2.…”

Section: Discussionmentioning

confidence: 99%

“…Experiments have shown that ciliobrevin A and D, which bind to AAA1, might bind to the AAA3 site [10]. In contrast, analogs of dynapyrazole, especially compound 20, abolished basal dynein activity by binding to the AAA3 and AAA4 [36]. Forty-six (46) analogs of ciliobrevin A and D were proposed to have potentially higher selectivity and potency than ciliobrevin A against dynein 2 [7].…”

Section: 1mentioning

confidence: 99%

See 1 more Smart Citation

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

Alisaraie

2021

Preprint

View full text Add to dashboard Cite

Dynein is a 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 AAA1 binding site is the leading ATP hydrolytic site, followed by the AAA3 subsite. Small-molecule ATP competitive inhibitors of dynein are thought to target the AAA1 site. The presented work elucidates the structure-activity relationship of dynapyrazole A and B, ciliobrevin A and D in their various protonated states and their 46 analogs for their binding properties in the nucleotide-binding site of the AAA1 subunit and their effects on the functionally essential subsites of the motor domain of cytoplasmic dynein 1, as there is currently no similar experimental structural data available. Ciliobrevin and its analogs bind to the ATP motifs of the AAA1, namely the Walker-A or P-loop, the Walker-B, and the sensor I and II. Ciliobrevin A shows a better binding affinity to the AAA1 binding site of dynein 1 than its D analog. 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. Protonation of the nitrogen in ciliobrevin A, D, 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, as the guanidine moiety of the Arg engages in an H-bond with the carboxylate moiety of Glu1849.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: 1mentioning

confidence: 99%

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

Alisaraie

2021

Preprint

View full text Add to dashboard Cite

show abstract

Role of motor proteins in human cancers

Ibrahim

Balah

Hassan

et al. 2022

Saudi Journal of Biological Sciences

View full text Add to dashboard Cite

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

Tati

Alisaraie

2021

IJMS

View full text Add to dashboard Cite

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.

show abstract

Targeting Allostery in the Dynein Motor Domain with Small Molecule Inhibitors

Cited by 3 publications

References 54 publications

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

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

Role of motor proteins in human cancers

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

Contact Info

Product

Resources

About