Biology subjects

Virta, P.

Publications and source records attributed to Virta, P..

2 recordsLinked to original sources

bioRxiv2025

Modulation of CIP2A dimerization and protein stability via druggable pocket

Cancerous inhibitor of PP2A (CIP2A) supports malignant growth across several cancer types. CIP2A is also a synthetic lethal therapy target for BRCA-mutant cancers. In addition, CIP2A causes Alzheime[r]s disease (AD) phenotype in mice. However, it is not dispensable for normal development and growth. Therefore, CIP2A is very lucrative therapy target in cancer and AD. So far it has been unclear whether the CIP2A protein harbors any druggable pockets amenable to targeting by small molecules. Here we discover a druggable pocket adjacent to the homodimerization domain of CIP2A. Mutagenesis demonstrates that pocket impacts CIP2A homodimerization, PP2A interaction, and full-length CIP2A protein stability in cancer cells. Further, we identify Gambogenic acid (GNA) as a tool compound that directly binds to CIP2A pocket region. GNA and its derivative Gambogic acid dissociate CIP2A homodimer in vitro and cause CIP2A destabilization in cellulo. The pocket contributes to the impact of GNA on homodimerization based on the protein fragment and mutagenesis analysis. These results identify structural vulnerability on CIP2A and may facilitate development of targeted CIP2A inhibitors with broad disease applicability.

biochemistry↗

bioRxiv2020

The mechanism of the nucleo-sugar selection by multi-subunit RNA polymerases

RNA polymerases (RNAPs) synthesize RNA from NTPs, whereas DNA polymerases synthesize DNA from 2’dNTPs. DNA polymerases select against NTPs by using steric gates to exclude the 2’ OH, but RNAPs have to employ alternative selection strategies. In single-subunit RNAPs, a conserved Tyr residue discriminates against 2’dNTPs, whereas selectivity mechanisms of multi-subunit RNAPs remain hitherto unknown. Here we show that a conserved Arg residue uses a two-pronged strategy to select against 2’dNTPs in multi-subunit RNAPs. The conserved Arg interacts with the 2’OH group to promote NTP binding, but selectively inhibits incorporation of 2’dNTPs by interacting with their 3’OH group to favor the catalytically-inert 2’-endo conformation of the deoxyribose moiety. This deformative action is an elegant example of an active selection against a substrate that is a substructure of the correct substrate. Our findings provide important insights into the evolutionary origins of biopolymers and the design of selective inhibitors of viral RNAPs.Competing Interest StatementThe authors have declared no competing interest.View Full Text

biochemistry↗