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Allosteric regulation of cathepsins and procathepsins enzymatic activity by glycosaminoglycans and their mimetics
The aim of the proposed project is to investigate at the molecular level mechanism of allosteric regulation of (pro)cathepsins activity by glycosaminoglycans. Cathepsins are predominantly cysteine proteases and can be found in extracellular matrix as well as in lysosomes. They are involved in many biological processes, including bone resorption, maintaining proper corneal physiology and integrin regulation. Their malfunction may lead to severe diseases, such as osteoporosis or Alzheimer's disease. Enzymatic activity of cathepsins may be regulated by glycosaminoglycans (GAGs), long unbranched periodic and negatively charged polisaccharides made up of recurring disaccharide unit. GAGs may regulate cathepsins activity in a process called allosteric regulation. Here cathepsin binds GAG molecule in a region other than its active site. Such binding leads to a conformational change of the active site, which makes cathepsin inactive. The detailed description of this mechanism with computational approaches will allow to propose novel molecules with similar effect, that could act as drugs for aforementioned diseases, which will be proposed in later stages of this project. Computational results obtained in this project will be experimentally verified by the group of Prof. Fabien Lecaille from the University of Tours. Additionally, this project will be performed in collaboration with group of prof. Martin Zacharias from Technical University of Munich. During this collaboration novel GAG mimetics and small drugs will be designed. Results of this project will be published in highly renowned journal as well as presented during international conferences.
Details
- Financial Program Name:
- SONATINA
- Organization:
- Narodowe Centrum Nauki (NCN) (National Science Centre)
- Agreement:
- UMO-2023/48/C/ST4/00163 z dnia 2023-12-01
- Realisation period:
- unknown - unknown
- Project manager:
- dr Krzysztof Bojarski
- Realised in:
- Department of Physical Chemistry
- Request type:
- National Research Programmes
- Domestic:
- Domestic project
- Verified by:
- Gdańsk University of Technology
Papers associated with that project
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Catalog Projects
Year 2024
-
In silico approaches for better understanding cysteine cathepsin-glycosaminoglycan interactions
PublicationCysteine cathepsins constitute the largest cathepsin family, with 11 proteases in human that are present primarily within acidic endosomal and lysosomal compartments. They are involved in the turnover of intracellular and extracellular proteins. They are synthesized as inactive procathepsins that are converted to mature active forms. Cathepsins play important roles in physiological and pathological processes and, therefore, receive...
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