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Projects / Programmes source: ARIS

Structural Biology

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Periods
January 1, 2014 - December 31, 2017
Research activity

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

Code Science Field
B000  Biomedical sciences   

Code Science Field
1.06  Natural Sciences  Biological sciences 
Evaluation (rules)
source: COBISS
Evaluation of bibliographic research performance indicators according to ARIS methodology
Citations Citations for bibliographic records in COBIB.SI that are linked to records in citation databases
source: WoS source: Scopus source: COBISS
Researchers (17)
no. Code Name and surname Research area Role Period No. of publications
1.  38853  Marjeta Arnolj    Technical associate  2016 - 2017  2 
2.  15970  Andreja Doberšek  Biochemistry and molecular biology  Technical associate  2014  25 
3.  06416  PhD Marko Dolinar  Biochemistry and molecular biology  Researcher  2014 - 2017  341 
4.  32503  PhD Katarina Karničar  Biotechnology  Researcher  2017  25 
5.  31952  PhD Nataša Lindič  Biochemistry and molecular biology  Researcher  2016 - 2017  32 
6.  39146  PhD Jure Loboda  Biochemistry and molecular biology  Junior researcher  2016 - 2017  50 
7.  36346  PhD Sara Pintar  Biochemistry and molecular biology  Junior researcher  2014 - 2017  20 
8.  19422  Polonca Pirš    Technical associate  2014 - 2017  0 
9.  24270  PhD Jure Pražnikar  Computer science and informatics  Researcher  2014 - 2017  39 
10.  34315  Gregor Pretnar    Technical associate  2015 - 2016  13 
11.  25629  PhD Miha Renko  Biochemistry and molecular biology  Researcher  2014  87 
12.  17096  Andreja Sekirnik  Biochemistry and molecular biology  Technical associate  2017  30 
13.  35125  PhD Abelardo Manuel Silva  Biochemistry and molecular biology  Researcher  2014  2 
14.  29544  PhD Ajda Taler Verčič  Biochemistry and molecular biology  Researcher  2014 - 2017  79 
15.  04988  PhD Dušan Turk  Biochemistry and molecular biology  Head  2014 - 2017  622 
16.  08773  PhD Livija Tušar  Biochemistry and molecular biology  Researcher  2014 - 2017  136 
17.  26515  PhD Aleksandra Usenik  Biochemistry and molecular biology  Researcher  2014 - 2017  54 
Organisations (2)
no. Code Research organisation City Registration number No. of publications
1.  0103  University of Ljubljana, Faculty of Chemistry and Chemical Technology  Ljubljana  1626990  23,103 
2.  0106  Jožef Stefan Institute  Ljubljana  5051606000  90,753 
Abstract
The proposed “Structural biology” program uses the structural information obtained from crystal structures of macromolecules and their complexes as the starting point to gain insight into molecular events at the atomic level. 3-dimensional atomic structures are used to link the information from the sequences of biological polymers with the role of individual residues in chemical mechanisms underlying physiological processes and their control. When exploring the structure of yet uncharacterized sequences with unassigned and unrecognized sequential motifs and patterns their discovery can expose functional roles of proteins or their domains. 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. In this process endosomal proteases and other hydrolytic enzymes generate candidates for antigenic presentation. Their selection occurs at two stages: by binding to the MHC class II molecules and their selection during recognition by the T-cells. As these physiological and pathological mechanisms are complex biological phenomena, we are integrating structural investigations with genomics, proteomics and other high throughput approaches often collaborating with groups in the region and around the world. The “Structural biology” program is a continuation of about a decade of research. Recently we established a platform for high-throughput, parallelized, partially automated approaches systems for protein expression, purification, crystallization and structure determination. This enables us to work simultaneously with groups of proteins, performing functional studies of experimental models with increasing complexity. We will continue to study endosomal proteins, in particular hydrolytic enzymes such as proteases, their targets from the surface of bacterial pathogens, MHC class II molecules, and the selection process of antigen presentation. Characterization of substrate specificity of enzymes is the current challenge of the field. In collaboration we are combining proteomics, combinatorial library screens, and structural approaches to understand the substrate specificity of cysteine cathepsins and legumain. Using this data we plan to determine the crystal structures of enzymes with bound representative peptidyl substrates obtained from the analysis of cleavage sites. Proteins from the surface of bacterial pathogens S. aureus, C. difficile, and E. fecali will be studied to gain insight into their structure, biochemical properties and effect on the cell wall. Our particular interest is to gain insight into the modular structure of C. difficile S-layer. Similarly we will study MHC class II molecules. Having all proteins at hand, we hope to be able to simulate the antigenic peptide selection process.
Significance for science
Remarkable progress in the world in the fields of biochemistry, molecular biology, cell biology, physiology and biophysics, allows a closer view in many processes of living organisms including humans. This opened new possibilities for a better understanding of the mechanism of action of biological molecules under normal and pathological conditions, where structural biology made a crucial contribution. The program Structural biology involves the preparation of recombinant proteins and their mutants in appropriate quantities. Proteins will be used in studies of molecular structures of biological macromolecules using the X-ray crystallography, 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 mankind. Understanding of immune response at a molecular level is the key factor in our defense against 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. Thus, 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, as 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 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 which was published in the prestigious journal Acta crystallogr. D, which is the first in the field. Previously, researchers  of this group mainly investigated the structure of cysteine ??proteases and their inhibitors stefins and cystatins, thus contributing to a better understanding of proteolysis in a wide sense, thus 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 prestigious universities and conferences.
Significance for the country
The development of structural biology started 40 years ago, however, in Slovenia we began to develop it in the last 20 years. This group made a significant contribution to the field with the determination of the first protein crystal structures in the country. Knowledge 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, Munich. The first crystal structures of cysteine cathepsins, their inhibitors stefins and cystatins, and the mechanism of their interactions were determined. With these achievements, the Slovenian researchers became recognized in their home country and internationally. They published a series of prominent publications with high citation rate including crystal structure of the complex cathepsin L-p41 Ii (EMBO J., 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. In the past it was an active cooperation with the pharmaceutical industry, 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 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 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 recent and pending investments in the equipment within the Centre of Excellence CIPKeBiP now brought the equipment and achievements to the competitive level of research (as demonstrated by in the invitation to present our work at Keystone Conference “High throughput Structural Biology” 2012, and one paper first in the field, 2013). However, the size of the team below the critical mass (4.7 FTE) and the reducing resources for covering of material costs of research (30% reduction in the last two years, the value of 1 FTE is about 65 000 EUR in 2013) 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.
Most important scientific results Annual report 2014, 2015, 2016, final report
Most important socioeconomically and culturally relevant results Annual report 2014, 2015, 2016, final report
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