Structural and Functional Characterization of the Immunoproteasome

Huber, E.M.

doi:10.1007/978-3-319-01556-9

Cited by 2 publications

(1 citation statement)

References 82 publications

(151 reference statements)

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“…Therefore, proteasome inhibitors are commonly classified by their characteristic "warhead" in seven classes (see Figure 1.9): aldehydes, boronic acids, α,β-epoxyketones, α-ketoaldehydes (glyoxals), vinyl sulfones, vinyl amides (syrbactins), and β-lactones. 178 Aldehydes (MG-132) have great value as research tools, but no medical potential due to their off-target activity towards serine and cysteine proteases. 158,174,179,180 Boronic acids are among the most potent inhibitors despite their high reactivity and associated side effects, bortezomib (PS-341) was synthesized with MG-132 as a lead compound and was the first approved proteasome inhibitor by the FDA.…”

Section: S Proteasome Inhibitionmentioning

confidence: 99%

Inhibition studies on the human 20S proteasome: molecular insights from a computational approach

Aparicio¹

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Section: S Proteasome Inhibitionmentioning

confidence: 99%

Inhibition studies on the human 20S proteasome: molecular insights from a computational approach

Aparicio¹

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Covalent Inhibition of the Human 20S Proteasome with Homobelactosin C Inquired by QM/MM Studies

2022

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20S proteasome is a main player in the protein degradation pathway in the cytosol, thus intervening in multiple pivotal cellular processes. Over the years the proteasome has emerged as a crucial target for the treatment of many diseases such as neurodegenerative diseases, cancer, autoimmune diseases, developmental disorders, cystic fibrosis, diabetes, cardiac diseases, atherosclerosis, and aging. In this work, the mechanism of proteasome covalent inhibition with bisbenzyl-protected homobelactosin C (hBelC) was explored using quantum mechanics/molecular mechanics (QM/MM) methods. Molecular dynamic simulations were used to describe key interactions established between the hBelC and its unique binding mode in the primed site of the β5 subunit. The free energy surfaces were computed to characterize the kinetics and thermodynamics of the inhibition process. This study revealed that although the final inhibition product for hBelC is formed according to the same molecular mechanism as one described for hSalA, the free energy profile of the reaction pathway differs significantly from the one previously reported for γ-lactam-β-lactone containing inhibitors in terms of the height of the activation barrier as well as the stabilization of the final product. Moreover, it was proved that high stabilization of the covalent adduct formed between β5-subunit and hBelC, together with the presence of aminocarbonyl side chain in the structure of the inhibitor which prevents the hydrolysis of the ester bond from taking place, determines its irreversible character.

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Structural and Functional Characterization of the Immunoproteasome

Cited by 2 publications

References 82 publications

Inhibition studies on the human 20S proteasome: molecular insights from a computational approach

Inhibition studies on the human 20S proteasome: molecular insights from a computational approach

Covalent Inhibition of the Human 20S Proteasome with Homobelactosin C Inquired by QM/MM Studies

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