Gutenberg Open Science

The Open Science Repository of Johannes Gutenberg University Mainz.

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Recent Submissions

ZeitschriftenaufsatzAccess status: Open Access ,
Conserved LIR-specific interaction of Sigma-1 receptor and GABARAP
(2025) Baeken, Marius Wilhelm; Christ, Maximilian; Schmitt, Daniel; Trein, Wencke; Nagel, Heike; Clement, Albrecht Martin; Körschgen, Hagen; Behl, Christian
Among its various functions, the sigma-1 receptor (σ1R) has been reported to modulate macroautophagy. It is currently unknown how this activity is mediated. We phylogenetically, structurally, and biochemically analyzed σ1R regarding its function in autophagy. We identified several putative LC3-interacting-regions (LIRs) that may mediate interactions with ATG8 proteins, which are known to promote autophagosome biogenesis, autophagic cargo reception, and lysosome fusion. Human σ1R comprises a LIR motif (hLIR5) typical for interaction with a specific ATG8, GABARAP. Biochemically, we uncovered a GABARAP-σ1R interaction depending on this motif via peptide array analysis and confirmed this via immunoprecipitation, co-localization, and proximity ligation assays. In addition, we verified a LIR-dependent presence of σ1R in isolated native autophagic vesicles. Excitingly, two point mutations within this LIR that have previously been reported to be associated with autosomal-recessive distal spinal muscular atrophy lack the ability to interact with GABARAP, highlighting the physiological relevance of the hLIR5-mediated σ1R-GABARAP interaction.
ZeitschriftenaufsatzAccess status: Open Access ,
DNA-encoded library screening uncovers potent DNMT2 inhibitors targeting a cryptic allosteric binding site
(2025) Frey, Ariane F.; Schwan, Merlin; Weldert, Annabelle C.; Kadenbach, Valerie; Kopp, Jürgen; Nidoieva, Zarina; Zimmermann, Robert A.; Gleue, Lukas; Zimmer, Collin; Jörg, Marko; Friedland, Kristina; Helm, Mark; Sinning, Irmgard; Barthels, Fabian
DNMT2 (TRDMT1) is a human RNA methyltransferase implicated in various disease processes. However, small-molecule targeting of DNMT2 remains challenging due to poor selectivity and low cellular availability of known S-adenosylhomocysteine (SAH)-derived ligands. In this study, a DNA-encoded library (DEL) screen identified five non-SAH-like chemotypes that selectively bind DNMT2, including three peptidomimetics. Orthogonal assays confirmed target engagement, and X-ray crystallography revealed a previously unknown allosteric binding pocket formed via active site loop rearrangement. Guided by structural insights, the authors optimized a lead compound with a KD of 3.04 μM that reduces m5C levels in MOLM-13 tRNA and synergizes with doxorubicin to impair cell viability. These inhibitors exhibit unprecedented selectivity over other methyltransferases, offering a promising scaffold for future DNMT2-targeting therapeutics. Beyond pharmacological implications, the study provides conceptual advances in understanding allosteric modulation and structural plasticity of DNMT2.
DissertationAccess status: Open Access ,
Nuclear structure corrections in muonic atoms
(2023) Li Muli, Simone Salvatore; Bacca, Sonia
Muonic hydrogen-like atoms, bound systems of a muon and an atomic nucleus, are excellent probes for nuclear physics, because the muon is much heavier than the electron and its wavefunction overlaps significantly more with the nuclear charge distribution. This increased sensitivity to nuclear physics allows for precise extractions of nuclear charge radii by measuring the Lamb-shift. The precision of this extraction is currently limited by the uncertainty of nuclear structure effects, which are not known as precisely as quantum electrodynamics effects, due to the non-perturbative nature of the strong force at the low-energy scale relevant to muonic atoms. This work addresses the calculation of the nuclear structure corrections to the Lamb-shift of muonic helium and lithium atoms. For muonic lithium, we calculate the nuclear structure corrections to the Lamb-shift using a simplified model of the nuclear force. This allows us to perform estimates, which are useful in view of the future planned experimental activities. For muonic helium, the novelty of this work comes from the use of nuclear interactions derived from the chiral effective field theory and of Bayesian inference for quantifying the uncertainties. This combination of techniques puts the problem of quantifying theoretical uncertainties in nuclear physics into a more solid statistical ground and defines a systematically improvable method for calculating observables. The main results of this work are new high-precision values for nuclear structure corrections in muonic atoms, which can be used to update the charge radii of 3 He and 4 He extracted from the recent muonic-atoms spectroscopy experiments in muonic helium. Due to partial cancellation of uncertainties, the squared difference in the nuclear charge radii, δr2 = rc2 (3 He) − rc2 (4 He) can be obtained with more precision than the nuclear charge radii itself. This quantity can also be precisely obtained from spectroscopy experiments in ordinary helium atoms, which allows to perform consistency checks between theory and experiments in electronic and muonic atoms. Two publications of δr2 , one using muonic atoms and the other using ordinary helium atoms, were recently published, which resulted in a disagreement at the level of 3.6σ. Our updated theory of the nuclear structure effects supports the previous value of δr2 coming from muonic atoms, and intensifies the current disagreement.