Midkine Interaction with Chondroitin Sulfate Model Synthetic Tetrasaccharides and Their Mimetics: The Role of Aromatic Interactions

Autor:	García-Jiménez, María José, Gil-Caballero, Sergio, Maza, Susana, Corzana, Francisco, Juárez-Vicente, Francisco, Miles, Jonathan R., Sakamoto, Kazuma, Kadomatsu, Kenji, García-Domínguez, Mario, de Paz, José L., Nieto, Pedro M., 0000-0002-4074-9011
Přispěvatelé:	Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España)
Rok vydání:	2021
Předmět:	Stereochemistry Oligosaccharides Hot Paper carbohydrate-protein complexes Catalysis Turn (biochemistry) chemistry.chemical_compound Mice Sulfation Animals Chondroitin sulfate transient NMRspectroscopy Glycosaminoglycans chondroitin sulfate Midkine chemistry.chemical_classification biology Full Paper Chemistry Ligand MD Organic Chemistry Chondroitin Sulfates Glycosidic bond General Chemistry Full Papers Docking (molecular) biology.protein NIH 3T3 Cells STD NMR spectroscopy Alpha helix
Zdroj:	Digital.CSIC: Repositorio Institucional del CSIC Consejo Superior de Investigaciones Científicas (CSIC) Chemistry (Weinheim an Der Bergstrasse, Germany) Digital.CSIC. Repositorio Institucional del CSIC instname RIUR. Repositorio Institucional de la Universidad de La Rioja
DOI:	10.1002/chem.202101674
Popis:	Midkine (MK) is a neurotrophic factor that participates in the embryonic central nervous system (CNS) development and neural stem cell regulation, interacting with sulfated glycosaminoglycans (GAGs). Chondroitin sulfate (CS) is the natural ligand in the CNS. In this work, we describe the interactions between a library of synthetic models of CS‐types and mimics. We did a structural study of this library by NMR and MD (Molecular Dynamics), concluding that the basic shape is controlled by similar geometry of the glycosidic linkages. Their 3D structures are a helix with four residues per turn, almost linear. We have studied the tetrasaccharide‐midkine complexes by ligand observed NMR techniques and concluded that the shape of the ligands does not change upon binding. The ligand orientation into the complex is very variable. It is placed inside the central cavity of MK formed by the two structured beta‐sheets domains linked by an intrinsically disordered region (IDR). Docking analysis confirmed the participation of aromatics residues from MK completed with electrostatic interactions. Finally, we test the biological activity by increasing the MK expression using CS tetrasaccharides and their capacity in enhancing the growth stimulation effect of MK in NIH3T3 cells. The spatial structures of the active complex of midkine and synthetic chondroitin sulfate tetrasaccharides have been solved by NMR spectroscopy and molecular dynamics simulations. The rigid ligand is enclosed by a flexible receptor, with an intrinsically disordered region. The 3D structure of the ligands remains as a helical, almost lineal structure, independently of the aromatic substituents introduced.
Databáze:	OpenAIRE
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