Structure of nevanimibe-bound tetrameric human ACAT1

Long, Tao; Sun, Yingyuan; Hassan, Abdirahman; Qi, Xiaofeng; Li, Xiaochun

doi:10.1038/s41586-020-2295-8

Cited by 72 publications

(96 citation statements)

References 41 publications

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“…The grids were imaged in a 300 keV Titan Krios (FEI) with a Gatan K3 Summit direct electron detector (Gatan) in super resolution mode using the data collection software Serial EM. Dark-subtracted images collected at super-resolution mode were first normalized by gain reference and binned twofold, which resulted in a pixel size of 0.833 Å with a counted rate of 23 electrons per physical pixel per second 40 . Images were recorded for 1.8 s exposures in 60 subframes with a total dose of 60 electrons per Å2 and a defocus range of −1.0 to −2.0 μm.…”

Section: Methodsmentioning

confidence: 99%

Molecular basis of V-ATPase inhibition by bafilomycin A1

et al. 2021

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Pharmacological inhibition of vacuolar-type H+-ATPase (V-ATPase) by its specific inhibitor can abrogate tumor metastasis, prevent autophagy, and reduce cellular signaling responses. Bafilomycin A1, a member of macrolide antibiotics and an autophagy inhibitor, serves as a specific and potent V-ATPases inhibitor. Although there are many V-ATPase structures reported, the molecular basis of specific inhibitors on V-ATPase remains unknown. Here, we report the cryo-EM structure of bafilomycin A1 bound intact bovine V-ATPase at an overall resolution of 3.6-Å. The structure reveals six bafilomycin A1 molecules bound to the c-ring. One bafilomycin A1 molecule engages with two c subunits and disrupts the interactions between the c-ring and subunit a, thereby preventing proton translocation. Structural and sequence analyses demonstrate that the bafilomycin A1-binding residues are conserved in yeast and mammalian species and the 7’-hydroxyl group of bafilomycin A1 acts as a unique feature recognized by subunit c.

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Section: Methodsmentioning

confidence: 99%

Molecular basis of V-ATPase inhibition by bafilomycin A1

et al. 2021

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“…Dark-subtracted images collected at super-resolution mode were first normalized by gain reference and binned twofold, which resulted in a pixel size of 0.833 Å with a counted rate of 23 electrons per physical pixel per second 48 . Images were recorded for 1.8-s exposures in 60 subframes with a total dose of 60 electrons per Å 2 and a defocus range of −1.0 to −2.0 μm.…”

Section: Methodsmentioning

confidence: 99%

Cryo-EM structures of intact V-ATPase from bovine brain

et al. 2020

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The vacuolar-type H +-ATPases (V-ATPase) hydrolyze ATP to pump protons across the plasma or intracellular membrane, secreting acids to the lumen or acidifying intracellular compartments. It has been implicated in tumor metastasis, renal tubular acidosis, and osteoporosis. Here, we report two cryo-EM structures of the intact V-ATPase from bovine brain with all the subunits including the subunit H, which is essential for ATPase activity. Two type-I transmembrane proteins, Ac45 and (pro)renin receptor, along with subunit c", constitute the core of the c-ring. Three different conformations of A/B heterodimers suggest a mechanism for ATP hydrolysis that triggers a rotation of subunits DF, inducing spinning of subunit d with respect to the entire c-ring. Moreover, many lipid molecules have been observed in the Vo domain to mediate the interactions between subunit c, c", (pro)renin receptor, and Ac45. These two structures reveal unique features of mammalian V-ATPase and suggest a mechanism of V1-Vo torque transmission.

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“…The structure of SOAT localized in the endoplasmic reticulum membrane had not been defined. Very recently, three research groups have just reported the structure of human-SOAT1 using cryo-electron microscopy [ 20 , 21 , 22 ]. Because SOAT1 and SOAT2 share extensive sequence homology, the structural properties of SOAT2 will be also elucidated in the near future.…”

Section: Discussionmentioning

confidence: 99%

New Terpendole Congeners, Inhibitors of Sterol O-Acyltransferase, Produced by Volutella citrinella BF-0440

et al. 2020

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New terpendoles N-P (1–3) were isolated along with 8 structurally related known compounds including terpendoles and voluhemins from a culture broth of the fungus Volutella citrinella BF-0440. The structures of 1–3 were elucidated using various spectroscopic experiments including 1D- and 2D-NMR. All compounds 1–3 contained a common indole–diterpene backbone. Compounds 2 and 3 had 7 and 6 consecutive ring systems with an indole ring, respectively, whereas 1 had a unique indolinone plus 4 consecutive ring system. Compounds 2 and 3 inhibited both sterol O-acyltransferase 1 and 2 isozymes, but 1 lost the inhibitory activity. Structure–activity relationships of fungal indole–diterpene compounds are discussed.

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Structure of nevanimibe-bound tetrameric human ACAT1

Cited by 72 publications

References 41 publications

Molecular basis of V-ATPase inhibition by bafilomycin A1

Molecular basis of V-ATPase inhibition by bafilomycin A1

Cryo-EM structures of intact V-ATPase from bovine brain

New Terpendole Congeners, Inhibitors of Sterol O-Acyltransferase, Produced by Volutella citrinella BF-0440

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