Structural insights into the modulation of PDGF/PDGFR-β complexation by hyaluronan derivatives
Author:
Balamurugan Kanagasabai1, Koehler Linda2, Dürig Jan-Niklas3, Hempel Ute4, Rademann Jörg3ORCID, Hintze Vera2ORCID, Pisabarro M. Teresa1
Affiliation:
1. Structural Bioinformatics, BIOTEC Technische Universität Dresden , Tatzberg 47-51 , D-01307 Dresden , Germany 2. Institute of Materials Science, Max Bergmann Center of Biomaterials, Technische Universität Dresden , Budapester Str. 27 , D-01069 Dresden , Germany 3. Medicinal Chemistry Department, Institute of Pharmacy, Freie Universität Berlin , Königin-Luise-Straße 2+4 , D-14195 Berlin , Germany 4. Institute of Physiological Chemistry, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden , Fiedlerstraße 42 , D-01307 Dresden , Germany
Abstract
Abstract
Angiogenesis is an important physiological process playing a crucial role in wound healing and cancer progression. Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are key players in angiogenesis. Based on previous findings regarding the modulation of VEGF activity by glycosaminoglycans (GAG), here we explore the interaction of hyaluronan (HA)-based GAG with PDGF and its receptor PDGFR-β by applying molecular modeling and dynamics simulations in combination with surface plasmon resonance (SPR). Computational analysis on the interaction of oligo-hyaluronan derivatives with different sulfation pattern and functionalization shows that these GAG interact with PDGF in relevant regions for receptor recognition, and that high sulfation as well as modification with the TAMRA group convey stronger binding. On the other hand, the studied oligo-hyaluronan derivatives are predicted to scarcely recognize PDGFR-β. SPR results are in line with the computational predictions regarding the binding pattern of HA tetrasaccharide (HA4) derivatives to PDGF and PDGFR-β. Furthermore, our experimental results also show that the complexation of PDGF to PDGFR-β can be modulated by HA4 derivatives. The results found open the path for considering HA4 derivatives as potential candidates to be exploited for modulation of the PDGF/PDGFR-β signaling system in angiogenesis and related disease conditions.
Publisher
Walter de Gruyter GmbH
Subject
Clinical Biochemistry,Molecular Biology,Biochemistry
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