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| Hauptseite > Publikationsdatenbank > Engineered human angiogenin mutations in the placental ribonuclease inhibitor complex for anticancer therapy: Insights from enhanced sampling simulations > print |
| Hauptseite > Publikationsdatenbank > Engineered human angiogenin mutations in the placental ribonuclease inhibitor complex for anticancer therapy: Insights from enhanced sampling simulations > print |
| 001 | 820508 | ||
| 005 | 20240625095121.0 | ||
| 024 | 7 | _ | |a 10.1002/pro.2941 |2 doi |
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| 037 | _ | _ | |a FZJ-2016-05801 |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Cong, Xiaojing |0 P:(DE-HGF)0 |b 0 |
| 245 | _ | _ | |a Engineered human angiogenin mutations in the placental ribonuclease inhibitor complex for anticancer therapy: Insights from enhanced sampling simulations |
| 260 | _ | _ | |a Hoboken, NJ |c 2016 |b Wiley |
| 336 | 7 | _ | |a article |2 DRIVER |
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| 520 | _ | _ | |a Targeted 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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| 700 | 1 | _ | |a Cremer, Christian |0 P:(DE-HGF)0 |b 1 |
| 700 | 1 | _ | |a Nachreiner, Thomas |0 P:(DE-HGF)0 |b 2 |
| 700 | 1 | _ | |a Barth, Stefan |0 P:(DE-HGF)0 |b 3 |e Corresponding author |
| 700 | 1 | _ | |a Carloni, Paolo |0 P:(DE-Juel1)145614 |b 4 |e Corresponding author |
| 773 | _ | _ | |a 10.1002/pro.2941 |g Vol. 25, no. 8, p. 1451 - 1460 |0 PERI:(DE-600)2000025-X |n 8 |p 1451 - 1460 |t Protein science |v 25 |y 2016 |x 0961-8368 |
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