I'm now studying proteasome and proteasome inhibitors such as MG132 and MG115.
I studied MG132 is a specific inhibitor of 26S proteasome but MG115 can inhibit both of 26S proteasome and 20S proteasome. However, i searched a lot of paper but no one illustrated how they work. I want know the exact mechanism of MG132 and MG115. There is any reference for this?
Actually MG115 and MG132, as well as the FDA-approved drugs bortezomib, carfilzomib, and ixazomib all act on the 20S proteasome at the level of the catalytic beta-subunits.
Since the 26S proteasome contains the 20S proteasome, 26S proteasomes will be inhibited too (at least their proteolytic activity will be).
All of these compounds bind to the catalytic beta subunits in the substrate binding site. Those subunits are beta1, beta2, and beta5, plus their immunoproteasome homologues beta1i, beta2i, and beta5i.
MG115 and MG132 both use an aldehyde chemical group as their 'warhead'. The nucleophilic oxygen atom of the catalytic Threonine-1 residue can attack the carbonyl carbon of the aldehyde to form a covalent complex.
Nowadays bortezomib is readily available online and is more potent and more metabolically stable than MG115 and MG132, so if you are doing cell-based work I would recommend using it.
Hope that helps, Zach Miller
Zachary Miller Thanks for your kind answer. So, you mean both MG132 and MG115 inhibit 26S proteasome via inhibition of catalytic beta subunit of 20S proteasome. Now i can understand.
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