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000820508 1001_ $$0P:(DE-HGF)0$$aCong, Xiaojing$$b0
000820508 245__ $$aEngineered human angiogenin mutations in the placental ribonuclease inhibitor complex for anticancer therapy: Insights from enhanced sampling simulations
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000820508 520__ $$aTargeted human cytolytic fusion proteins (hCFPs) represent a new generation of immunotoxins (ITs) for the specific targeting and elimination of malignant cell populations. Unlike conventional ITs, hCFPs comprise a human/humanized target cell-specific binding moiety (e.g., an antibody or a fragment thereof) fused to a human proapoptotic protein as the cytotoxic domain (effector domain). Therefore, hCFPs are humanized ITs expected to have low immunogenicity. This reduces side effects and allows long-term application. The human ribonuclease angiogenin (Ang) has been shown to be a promising effector domain candidate. However, the application of Ang-based hCFPs is largely hampered by the intracellular placental ribonuclease inhibitor (RNH1). It rapidly binds and inactivates Ang. Mutations altering Ang's affinity for RNH1 modulate the cytotoxicity of Ang-based hCFPs. Here we perform in total 2.7 µs replica-exchange molecular dynamics simulations to investigate some of these mutations—G85R/G86R (GGRRmut), Q117G (QGmut), and G85R/G86R/Q117G (GGRR/QGmut). GGRRmut turns out to perturb greatly the overall Ang-RNH1 interactions, whereas QGmut optimizes them. Combining QGmut with GGRRmut compensates the effects of the latter. Our results explain the in vitro finding that, while Ang GGRRmut-based hCFPs resist RNH1 inhibition remarkably, Ang WT- and Ang QGmut-based ones are similarly sensitive to RNH1 inhibition, whereas Ang GGRR/QGmut-based ones are only slightly resistant. This work may help design novel Ang mutants with reduced affinity for RNH1 and improved cytotoxicity.
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000820508 7001_ $$0P:(DE-HGF)0$$aCremer, Christian$$b1
000820508 7001_ $$0P:(DE-HGF)0$$aNachreiner, Thomas$$b2
000820508 7001_ $$0P:(DE-HGF)0$$aBarth, Stefan$$b3$$eCorresponding author
000820508 7001_ $$0P:(DE-Juel1)145614$$aCarloni, Paolo$$b4$$eCorresponding author
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