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DNA G-quadruplexes play important roles in biological processes and have been identified as promising drug targets, e.g. in anticancer research. In an interdisciplinary collaboration between the laboratories of Prof. Guido Clever and Jun.-Prof. Müge Kasanmascheff, both at TU Dortmund University, a method for the precise distance measurement in pairs of G-quadruplexes with or without bound drug-like molecules was developed. The remarkable accuracy of this method allows elucidating the structure of such DNA adducts and provides evidence for intercalated compounds.
Human DNA usually adopts a helical, double stranded structure. However, also four-stranded variants (so-called G‑quadruplexes) are known to form from guanine-rich sequences, resembling columnar stacks. In the past years, more and more evidence for biological functions and medicinal relevance of these DNA species was revealed. To understand the role of G‑quadruplexes in the body, their architecture and structure must be elucidated. This is a challenging task, since these special DNA motifs show a high structural diversity. Once spatial structure and biological function are unraveled, small molecules can be specifically designed to bind to these G‑quadruplexes and manipulate their function. Since G‑quadruplexes are thought to play crucial roles in different cancer types and also HIV infection and Malaria, such DNA-binding molecules may show potential application as drugs.
In addition, G‑quadruplexes are known to form higher-ordered structures. For example, they can assemble pairwise and form so-called dimers. Intercalation of small, usually flat molecules into these dimers results in sandwich complexes. It has been difficult to reveal the formation of these nanometer-sized dimers and sandwich structures and even more so to measure their spatial dimension. In close cooperation, the research groups of Jun.-Prof. Müge Kasanmascheff and Prof. Guido Clever at TU Dortmund University have recently been successful in developing a method that allows detecting such structures in solution with unprecedented accuracy.
A strategy including the precise incorporation of copper ions into chemically modified DNA G‑quadruplexes enables distance measurements between unpaired electrons in both halves of the G-quadruplex dimers by a technique called EPR spectroscopy. Small molecules, usually not soluble in water, were intercalated into the dimers in aqueous solution, resulting in a characteristically increased distance between the copper complexes. Due to the tight and rigid binding of the copper ions in the G‑quadruplexes, distances were obtained with remarkable precision.
The project was realized within the RESOLV cluster of excellence funded by the German Research Foundation (DFG) and recently published as an open access paper in the journal Angewandte Chemie. It was selected as a Very Important Paper. The presented method is of particular importance for structure elucidation of DNA G-quadruplex adducts and promises to facilitate the search for novel pharmacologically active molecules.
“Precise Distance Measurements in DNA G‐Quadruplex Dimers and Sandwich Complexes by Pulsed Dipolar EPR Spectroscopy”
L. M. Stratmann, Y. Kutin, M. Kasanmascheff, G. H. Clever, Angew. Chem. Int. Ed. 2020, accepted, DOI: 10.1002/anie.202008618 (VIP Paper)
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The campus of TU Dortmund University is located close to interstate junction Dortmund West, where the Sauerlandlinie A 45 (Frankfurt-Dortmund) crosses the Ruhrschnellweg B 1 / A 40. The best interstate exit to take from A 45 is “Dortmund-Eichlinghofen” (closer to South Campus), and from B 1 / A 40 “Dortmund-Dorstfeld” (closer to North Campus). Signs for the university are located at both exits. Also, there is a new exit before you pass over the B 1-bridge leading into Dortmund.
To get from North Campus to South Campus by car, there is the connection via Vogelpothsweg/Baroper Straße. We recommend you leave your car on one of the parking lots at North Campus and use the H-Bahn (suspended monorail system), which conveniently connects the two campuses.
TU Dortmund University has its own train station (“Dortmund Universität”). From there, suburban trains (S-Bahn) leave for Dortmund main station (“Dortmund Hauptbahnhof”) and Düsseldorf main station via the “Düsseldorf Airport Train Station” (take S-Bahn number 1, which leaves every 20 or 30 minutes). The university is easily reached from Bochum, Essen, Mülheim an der Ruhr and Duisburg.
You can also take the bus or subway train from Dortmund city to the university: From Dortmund main station, you can take any train bound for the Station “Stadtgarten”, usually lines U41, U45, U 47 and U49. At “Stadtgarten” you switch trains and get on line U42 towards “Hombruch”. Look out for the Station “An der Palmweide”. From the bus stop just across the road, busses bound for TU Dortmund University leave every ten minutes (445, 447 and 462). Another option is to take the subway routes U41, U45, U47 and U49 from Dortmund main station to the stop “Dortmund Kampstraße”. From there, take U43 or U44 to the stop “Dortmund Wittener Straße”. Switch to bus line 447 and get off at “Dortmund Universität S”.
The AirportExpress is a fast and convenient means of transport from Dortmund Airport (DTM) to Dortmund Central Station, taking you there in little more than 20 minutes. From Dortmund Central Station, you can continue to the university campus by interurban railway (S-Bahn). A larger range of international flight connections is offered at Düsseldorf Airport (DUS), which is about 60 kilometres away and can be directly reached by S-Bahn from the university station.
The H-Bahn is one of the hallmarks of TU Dortmund University. There are two stations on North Campus. One (“Dortmund Universität S”) is directly located at the suburban train stop, which connects the university directly with the city of Dortmund and the rest of the Ruhr Area. Also from this station, there are connections to the “Technologiepark” and (via South Campus) Eichlinghofen. The other station is located at the dining hall at North Campus and offers a direct connection to South Campus every five minutes.
The facilities of TU Dortmund University are spread over two campuses, the larger Campus North and the smaller Campus South. Additionally, some areas of the university are located in the adjacent “Technologiepark”.