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Projects / Programmes source: ARIS

Structural Biology

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Periods
January 1, 2018 - December 31, 2027
Research activity

Code Science Field Subfield
1.05.00  Natural sciences and mathematics  Biochemistry and molecular biology   
4.06.00  Biotechnical sciences  Biotechnology   

Code Science Field
B000  Biomedical sciences   

Code Science Field
1.06  Natural Sciences  Biological sciences 
3.04  Medical and Health Sciences  Medical biotechnology 
Keywords
Structural biology Adaptive immunity Antigen Protein degradation MHC class II molecules cystein cathepsins
Evaluation (rules)
source: COBISS
Evaluation of bibliographic research performance indicators according to ARIS methodology
Points
2,082.16
A''
405.31
A'
1,172.89
A1/2
1,589.2
CI10
6,417
CImax
829
h10
41
A1
7.66
A3
2.96
Data for the last 5 years (citations for the last 10 years) on April 24, 2024; A3 for period 2018-2022
Data for ARIS tenders ( 04.04.2019 – Programme tender , archive )
Citations Citations for bibliographic records in COBIB.SI that are linked to records in citation databases
source: WoS source: Scopus source: COBISS
Database Linked records Citations Pure citations Average pure citations
WoS  240  13,400  11,619  48.41 
Scopus  220  13,653  11,874  53.97 
Researchers (21)
no. Code Name and surname Research area Role Period No. of publications
1.  06416  PhD Marko Dolinar  Biochemistry and molecular biology  Researcher  2018 - 2024  341 
2.  56663  Klemen Dretnik  Biochemistry and molecular biology  Junior researcher  2022 - 2024  0 
3.  38323  Marinka Horvat  Biotechnology  Technical associate  2020 - 2024  0 
4.  32503  PhD Katarina Karničar  Biotechnology  Researcher  2018 - 2024  25 
5.  52369  Ana Kump  Biochemistry and molecular biology  Researcher  2022 - 2024  40 
6.  53528  PhD Jasna Lalić  Biochemistry and molecular biology  Researcher  2019  1 
7.  31952  PhD Nataša Lindič  Biochemistry and molecular biology  Researcher  2018 - 2024  32 
8.  39146  PhD Jure Loboda  Biochemistry and molecular biology  Researcher  2018 - 2023  50 
9.  37797  PhD Georgy Mikhaylov  Biochemistry and molecular biology  Researcher  2018  54 
10.  53532  Matej Novak  Biochemistry and molecular biology  Junior researcher  2019 - 2024  5 
11.  55509  Tjaša Peternel    Technical associate  2021 - 2022  4 
12.  36346  PhD Sara Pintar  Biochemistry and molecular biology  Researcher  2018 - 2020  20 
13.  19422  Polonca Pirš    Technical associate  2018 - 2024  0 
14.  24270  PhD Jure Pražnikar  Computer science and informatics  Researcher  2018 - 2024  39 
15.  17096  Andreja Sekirnik  Biochemistry and molecular biology  Technical associate  2018 - 2024  30 
16.  35125  PhD Abelardo Manuel Silva  Biochemistry and molecular biology  Researcher  2018 - 2019  2 
17.  29544  PhD Ajda Taler Verčič  Biochemistry and molecular biology  Researcher  2018 - 2019  79 
18.  04988  PhD Dušan Turk  Biochemistry and molecular biology  Head  2018 - 2024  622 
19.  08773  PhD Livija Tušar  Biochemistry and molecular biology  Researcher  2018 - 2024  136 
20.  26515  PhD Aleksandra Usenik  Biochemistry and molecular biology  Researcher  2018 - 2024  54 
21.  53274  Viktor Zupančič  Biotechnology  Junior researcher  2021 - 2022  0 
Organisations (2)
no. Code Research organisation City Registration number No. of publications
1.  0106  Jožef Stefan Institute  Ljubljana  5051606000  90,724 
2.  0103  University of Ljubljana, Faculty of Chemistry and Chemical Technology  Ljubljana  1626990  23,091 
Abstract
The proposed “Structural biology” program follows the premise that physiological processes can be reproduced in vitro once we know all molecular components and understand their properties and interactions. Such understanding requires insight in the molecular mechanisms from the points of view of structural, molecular, and computational biology. It is the atomic 3-dimensional structures of macromolecules in particular that link the information from the sequences of biological polymers with the role of individual residues in biophysical and chemical mechanisms underlying physiological processes. The main biological theme of the proposed research is the process of adaptive immunity, where organism learns to discriminate between self and non-self proteins as a specific defense against invading microorganisms and their own misbehaved cells. This process begins with antigen presentation. Peptidyl candidates for antigenic presentation are generated by degradation of foreign proteins by endosomal proteases and other hydrolytic enzymes and continue with two level selection process, including binding to the MHC class II molecules and recognition of the formed complexes by the T-cells. The “Structural biology” program is a continuation of a decade of our research. Recently, we established a platform for high-throughput, parallelized, and semi-automated protein expression, purification, crystallization, and structure determination. This pipeline enables us to work simultaneously with groups of proteins, performing functional studies of experimental models with increasing complexity. In addition to continuing to study endosomal proteases, we will also study other endosomal enzymes, MHC class II molecules, their targets from the surface of bacterial pathogens Staphylococcus aureus, Clostridium difficile, and Enterococcus faecalis, and the selection process of antigen presentation. We aim to elucidate what makes a protein substrate of a cysteine cathepsin and to develop a method to predict this property. We expect that 3D structure of MHC class II molecules in complex with invariant chain will provide clues that will enable us to interpret in detail the complicated mechanism of invariant chain processing that occurs simultaneously with proteolytic degradation of antigenic proteins. We expect that continuation of our studies of proteins from pathogenic bacteria involved in the structure and remodeling of surface assemblies, such as S-layer, peptidoglycan cell wall, and biofilms, will help us to explore their potential as targets for novel anti-bacterial therapies. To pursue our goals, we will use biochemistry, molecular and cell biology, macromolecular crystallography, electron microscopy, small angle X-ray scattering, organic synthesis, proteomics, and computational biology. Such broad spectrum of technologies can only be applied within an extensive local and international network of collaborators.
Significance for science
Remarkable progress in the fields of biochemistry, molecular biology, cell biology, physiology, biophysics, and structural biology enables insight in many processes of living organisms including humans, at unforeseen levels. The opened possibilities are resulting in better understanding of mechanisms of action of biological molecules under normal and pathological conditions. The program “Structural biology” involves preparation of recombinant proteins and their mutants in appropriate quantities. Proteins are used in studies of molecular structures of biological macromolecules using the X-ray crystallography and electron microscopy, in order to understand their mechanisms of action at the molecular and atomic levels. The impact of the replacement of specific amino acids on the protein function will be evaluated. The understanding of mechanisms of biological processes is the basis, which allows targeted manipulation of biological systems with foreseen consequences and thereby enables the use of knowledge for the development of new products such as chemotherapeutics for the benefit of the humankind.   Understanding of immune response at the molecular level can turn into our key factor in treatment of infectious and autoimmune diseases and diseases such as cancer, which can hide from the immune system. Elucidation of players and characterization of individual interactions among them may help to deliver therapeutics for treatment and prevention of such diseases. Therefore, research targeting the key players of the mechanisms of the adaptive immunity is one of the most developed and cutting edge research areas in the world. Consequently, this research leads to the rational design of protease inhibitors as drugs for cancer and other diseases. This research program shows that the investigated proteins are closely related to medicine and, possibly, candidates for treatment of various diseases. Moreover, the program of Structural biology includes cooperations with groups in the region and abroad, covering the areas of protein folding, electron microscopy and various spectroscopic methods.   For the implementation of complex tasks of structural biology and macromolecular crystallography, the group will continue with parameters for force field development, refinement techniques and concepts. It is also important to mention the interactive computer program MAIN, developed by the PI. Previously, researchers of this group mainly investigated the structure of cysteine proteases and their protein inhibitors, thus contributing to a better understanding of proteolysis in a wide sense and thereby contributing to the affirmation of Slovenian science in the world. This is evident from the quality of their publications and numerous citations, as well as invited lectures at numerous universities, research institutes and conferences.
Significance for the country
In 1934, the beginnings of structural biology were established by Dorothy Hodgkin. She invented and started using the X-ray diffraction for the imaging of the protein crystals. The first protein structure ever was unveiled in 1958 by John Kendrew. The protein was myoglobin. In Slovenia, the structural biology began to develop 25 years ago at Jozef Stefan Institute. The first major step forward in in this field was gained by the PI of this program working on his PhD thesis with Nobel laureate Robert Huber at the Max-Planck Institute in Martinsried, Münich. In 1996, he established the Structural biology group at the Jožef Stefan Institute. The first crystal structures discovered by this group were structures of cysteine cathepsins, their inhibitors stefins (named after Jožef Stefan Institute) and cystatins, also the mechanism of their interactions was determined. They published a series of prominent publications with high citation rate including crystal structure of the complex cathepsin L- Ii p41 (Guncar et al, 1999). They became a worldwide recognized group, thus contributing to the reputation of Slovenian science. Later, they also participated in the EU Framework Programmes. The obtained knowledge shows potential in the pharmaceutical industry and biotech SMEs. The second step forward was an active cooperation with the pharmaceutical industry in the past, which contributed significantly to the purchase of equipment. This research provided the basis of structural biology at the Jožef Stefan Institute, University of Ljubljana, University of Primorska, and the International Postgraduate School IJS. The research work resulted in several doctoral dissertations, master's and bachelor's degrees. Former students and employees are currently employed in industry, other institutes, universities, administration (such as EU) or abroad. Lack of investment in the past has had a serious impact on our research. Development in this area is linked to significant investment in research itself, as well as in infrastructure for protein production, crystallization and structure determination. The third step forward was in 2010 when the group had actively participated at the development of the Centre of excellence for integrated approaches in chemistry and biology of proteins CIPKeBiP. CIPKeBiP with its infrastructural platforms has enabled the Structural biology group to bring the achievements to the competitive level of research (as demonstrated by in the recent publications Sosnowski & Turk 2016, Usenik et al 2017, Mihelic et al 2017). However, the size of the team below the critical mass (4.7 FTE) and the reducing resources for covering of material costs of research are now a serious limitation to perform research at the international competitive level. Nevertheless, our achievements contributed to the development of structural biology in Slovenia and internationally.
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