Kai Tittmann

University of Göttingen

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Ralph Golbik

Martin Luther University Halle-Wittenberg

Gerhard Hübner

Borealis (Austria)

Fabian Rabe von Pappenheim

University of Göttingen

V. Sautner

Max Planck Institute for Biophysical Chemistry

Danilo Meyer

Leibniz Institute of Plant Biochemistry

Ricardo A. Mata

University of Göttingen

Ralf Ficner

University of Göttingen

Piotr Neumann

University of Göttingen

Lisa-Marie Funk

University of Göttingen

C. Parthier

Martin Luther University Halle-Wittenberg

Cooperative Institutions

University of Göttingen

Martin Luther University Halle-Wittenberg

Child Trends

Max Planck Institute for Biophysical Chemistry

Max Planck Institute for Multidisciplinary Sciences

Max Planck Society

University of Freiburg

University of Utah

Universitätsmedizin Göttingen

University at Buffalo, State University of New York

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Structural and Functional Analyses of the Human PDH Complex Suggest a “Division-of-Labor” Mechanism by Local E1 and E3 Clusters

Structure (2019)

Sabin Prajapati David Haselbach Sabine Wittig Mulchand S. Patel Ashwin Chari

10.1016/j.str.2019.04.009

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Citations (28)

Crystal structure of a short-chain dehydrogenase/reductase (SDR) from Zephyranthes treatiae in complex with NADP+

V. Sautner Simon Steimle Sebastian Roth Michael Mueller Kai Tittmann

10.2210/pdb6y4d/pdb

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Citations (0)

Crystal structure of human glutaminyl cyclase in complex with neurotensin 1-5

Lisa-Marie Funk V. Sautner Kai Tittmann

10.2210/pdb6yjy/pdb

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Citations (0)

Transketolase from E. coli in complex with substrate D-fructose-6-phosphate

Georg Wille P. Asztalos M.S. Weiss Kai Tittmann

Transketolase

10.2210/pdb2r8o/pdb

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PtdInsP2 and PtdSer cooperate to trap synaptotagmin-1 to the plasma membrane in the presence of calcium

eLife (2016)

Ángel Pérez-Lara Anusa Thapa Sarah B. Nyenhuis David A. Nyenhuis Partho Halder

The Ca2+-sensor synaptotagmin-1 that triggers neuronal exocytosis binds to negatively charged membrane lipids (mainly phosphatidylserine (PtdSer) and phosphoinositides (PtdIns)) but the molecular details of this process are not fully understood. Using quantitative thermodynamic, kinetic and structural methods, we show that synaptotagmin-1 (from Rattus norvegicus and expressed in Escherichia coli) binds to PtdIns(4,5)P2 via a polybasic lysine patch in the C2B domain, which may promote the priming or docking of synaptic vesicles. Ca2+ neutralizes the negative charges of the Ca2+-binding sites, resulting in the penetration of synaptotagmin-1 into the membrane, via binding of PtdSer, and an increase in the affinity of the polybasic lysine patch to phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2). These Ca2+-induced events decrease the dissociation rate of synaptotagmin-1 membrane binding while the association rate remains unchanged. We conclude that both membrane penetration and the increased residence time of synaptotagmin-1 at the plasma membrane are crucial for triggering exocytotic membrane fusion.

Synaptotagmin 1

10.7554/elife.15886

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Citations (106)

Activation of thiamin diphosphate in enzymes

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics (1998)

Gerhard Hübner Kai Tittmann Margrit Killenberg‐Jabs Jörg Schäffner Michael Spinka

Pyruvate decarboxylase

Transketolase

Dihydrolipoyl transacetylase

10.1016/s0167-4838(98)00070-3

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Citations (50)

NOS and SONOS redox switches in proteins

Research Square (Research Square) (2021)

Fabian Rabe von Pappenheim Marie Wensien Ye Jin Jon Uranga Lisa-Marie Funk

Abstract We recently reported on the discovery of a lysine-cysteine redox switch in proteins with a covalent NOS bridge. Here, a systematic survey of the whole protein structure database discloses that NOS bridges are ubiquitous, hitherto overlooked redox switches in proteins of all domains of life and are found in diverse structural motifs and chemical variants. In several instances, lysines are observed in simultaneous linkage with two cysteines forming a SONOS bridge with a trivalent nitrogen, which constitutes the first native branching crosslink in proteins. In many proteins, the NOS switch contains a functionally essential lysine with direct roles in enzyme catalysis or binding of substrates, DNA or effectors linking lysine chemistry and redox biology as a novel regulatory principle. The NOS/SONOS switches are frequently found in proteins from human and plant pathogens including i.a. SARS-CoV-2 but also in many human proteins with established roles in gene expression, redox signaling and homeostasis in both physiological and pathophysiological conditions. Targeting, mimicking, controlling and engineering the NOS and SONOS redox switches appear to open novel avenues in drug, antiviral, antibiotic and herbicide development, in biocatalytic applications as well as in protein design and bioorganic chemistry.

10.21203/rs.3.rs-635771/v1

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Sub-ångström-resolution crystallography reveals physical distortions that enhance reactivity of a covalent enzymatic intermediate

Nature Chemistry (2013)

Stefan Lüdtke P. Neumann Karl M. Erixon Finian J. Leeper Ronald Kluger

Transketolase

10.1038/nchem.1728

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Citations (78)

The catalytic cycle of a thiamin diphosphate enzyme examined by cryocrystallography

Nature Chemical Biology (2006)

Georg Wille Danilo Meyer Andrea Steinmetz Erik Hinze Ralph Golbik

Decarboxylation

Catalytic cycle

Enzyme Catalysis

Oxidative decarboxylation

Reaction intermediate

Pyruvate decarboxylase

10.1038/nchembio788

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Citations (111)

Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design

Nature Communications (2024)

Lisa-Marie Funk Gereon Poschmann Fabian Rabe von Pappenheim Ashwin Chari Kim M. Stegmann

Abstract Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for preventing future COVID outbreaks. The SARS-CoV-2 main protease (M pro ), a cysteine protease with essential functions in viral replication, has been validated as an effective drug target. Here, we show that M pro is subject to redox regulation in vitro and reversibly switches between the enzymatically active dimer and the functionally dormant monomer through redox modifications of cysteine residues. These include a disulfide-dithiol switch between the catalytic cysteine C145 and cysteine C117, and generation of an allosteric cysteine-lysine-cysteine SONOS bridge that is required for structural stability under oxidative stress conditions, such as those exerted by the innate immune system. We identify homo- and heterobifunctional reagents that mimic the redox switching and inhibit M pro activity. The discovered redox switches are conserved in main proteases from other coronaviruses, e.g. MERS-CoV and SARS-CoV, indicating their potential as common druggable sites.

Druggability

Cysteine protease

10.1038/s41467-023-44621-0

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Citations (14)