Dokument: Integrative modeling of function-associated molecular recognition in protein-ligand, protein-peptide, and protein-protein complexes

Titel:	Integrative modeling of function-associated molecular recognition in protein-ligand, protein-peptide, and protein-protein complexes
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=52077
URN (NBN):	urn:nbn:de:hbz:061-20200128-092354-6
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Frieg, Benedikt [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 137,80 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 23.01.2020 / geändert 23.01.2020
Beitragende:	Prof. Dr. Gohlke Holger [Gutachter] Jun.-Prof. Strodel, Birgit [Gutachter]
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 540 Chemie
Beschreibung:	Molecular recognition describes the process of how biological macromolecules interact with each other or with smaller molecules to form a complex with a biological function. The complex is thus a product of high specificity and affinity. In many cases, enzymatic mal-function is often induced by a change in the affinity or specificity between the interaction partners. An in-depth understanding of the fundamental recognition processes can help to answer so far unresolved biological and medical questions. To study these fundamental recognition processes, I employed computer-aided methods, which are summarized under the term "computational microscopy". A fundamental aspect of this work, however, is that the results of the simulations were always linked to experimental data in the sense of integrative modeling. Hence, experiments were used to refine and validate my computational results. Alternatively, I was able to use my computer-aided methods to explain experimental observations at the functional level in atomic resolution. In particular, I investigated the molecular regulation and inhibition mechanisms of the human glutamine synthetase, an enzyme essential for the human nitrogen metabolism. Loss of enzymatic activity is associated with severe clinical conditions. In the present work, I found that both innate enzyme variations and tyrosine nitration adversely affect the affinity of the glutamine synthetase to its substrates. The reduced affinity provides a plausible explanation for the associated loss of enzymatic activity (PUBLICATION I and PUBLICATION II). The results may also help to develop new strategies to restore the initial affinity of the glutamine synthetase towards its substrates. Highly specific interactions between an enzyme and a substrate play an important role in the development of resistance mechanisms to antibacterial substances. For example, in the course of resistance development Streptococcus agalactiae produces the resistance protein NSR, which binds and cleaves antibacterial nisin. The cleaved nisin, however, is antibacterial ineffective. In the present work, I found how and why NSR specifically recognizes nisin (PUBLICATION III). These insights form the basis for the identification of potential NSR inhibitors to prevent nisin inactivation. The actual process of binding of two molecules can be described by two individual steps; first, both molecules move freely and only when both molecules approach each other does a complex form as a result of high specificity and affinity. In PUBLICATION IV, I succeeded in reconstructing the binding process of the novel, first-in-class anticancer com-pound Aminoxyrone to its receptor. The insights suggest a new and previously unknown mode of action. This work thus forms the basis for the development of new compounds in cancer therapy, which follow the same mode of action as Aminoxyrone.
Lizenz:	Urheberrechtsschutz
Fachbereich / Einrichtung:	Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische und Medizinische Chemie
Dokument erstellt am:	28.01.2020
Dateien geändert am:	28.01.2020
Promotionsantrag am:	07.06.2019
Datum der Promotion:	21.11.2019