Projects / Programmes
Membranski proteini - od statističnih modelov do strukture in mehanizma transporta (Slovene)
| Code |
Science |
Field |
Subfield |
| 1.04.02 |
Natural sciences and mathematics |
Chemistry |
Structural chemistry |
| Code |
Science |
Field |
| 1.04 |
Natural Sciences |
Chemical sciences |
Researchers (7)
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0104 |
National Institute of Chemistry |
Ljubljana |
5051592000 |
21,007 |
Significance for science
The information about a 3D structure of a membrane protein is of great importance in the study of the protein transport mechanism. However, less than 1 % of structures out of approximately 30000 protein structures found in the Protein Data Bank (PDB), belong to membrane proteins. In the absence of the experimentally obtained 3D structures, every information obtained from in-silico approach is valuable.
The project research objectives, such as enrichment of experimental data on the transport activity of bilitranslocase (BTL) for structurally diverse compounds, data-driven model for prediction of BTL inhibition constants, model for grouping, classification and prediction of trans-membrane domains of membrane transport proteins, NMR experiments for comparison of predicted 3D structure of trans-membrane domains of membrane transport proteins, and bio-molecular simulations (QM/MM, MD) of bilitranslocase will help us getting insight into the binding sites of trans-membrane proteins, such as bilitranslocase, as well as to identify the structural fragments of the ligands involved in the transport mechanism studied in the particular biological system. Structural analysis of BTL has so far demonstrated that the four segments, about 20 amino acids long, are embedded in the cell membrane, two loops are outside, the beginning and end of the protein (N-terminal and C-terminal) are located within the cell. Regarding the mechanism of transport, we confirmed a strong role for the formation of hydrogen bonds and conformational changes of proline containing transmembrane segments.
It has been found out that bilitranslocase transports certain antioxidants such as flavonols, especially anthocyanins, and nicotinic acid through the cell membrane. BTL is involved in transport of some of nucleotides and nucleosides, which is particularly important for blood cleansing function of the degradation products in liver cells. Detailed knowledge of the transport mechanism will allow us to identify selective inhibitors, such as in fostering the transfer of flavonols, but hold up the transfer of nicotinic acid. We collected evidence that bilitranslocase might be a drug transporter.
The mechanism of transport might be explained by conformational changes of two proline containing transmembrane segments, TM2 in TM3. The helix breaker proline can be in cis or trans form, which enables opening and closing of the pore which allows the polar molecules to pass the membrane. The knowledge about the mechanism of transport of bilitranslocase would be of crucial importance for drug development, since this protein has been identified as potential drug target. The publication of the first study on 3D structure of transmembrane domains of a membrane transporter bilitranslocase ((PLoS ONE, 2012; 7(6): e38967. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0038967) attracted the attention of the Target Selection team of Global Medical Discovery Series, who invited us to prepare a short summary for a scientific allert (http://globalmedicaldiscovery.com/key-scientific-articles/structural-analysis-of-a-peptide-fragment-of-transmembrane-transporter-protein-bilitranslocase/).
Significance for the country
Project »Membrane proteins - from statistics models towards structure and mechanism of transport« represents the research in the directions of the EU research priorities, as well as priorities of Slovenian research policy - for the research of genomics and health-related biotechnology; food safety and quality; sustainable development. The membrane transport is important in chemical and biological studies of proteins, cellular biology, biotechnology, biomedical research, and chemical biology. The new knowledge about the membrane proteins is important for the development of drugs, as well as for the optimizations employed by pharmaceutical industry directed towards generic drugs.
Nowadays the natural products with beneficial effect for human health, such as antioxidants, are becoming widely exploited and offer a possibility for new companies (SME). The results from this project might help finding a chemical modification of a particular antioxidant compound to better penetrate through the cellular membrane with help of bilitranslocase transport mechanism.
Among the results of this project is also the development of QSA(P)R models. These results can be additionally exploited in the information technology (IT) community interested in (Q)SARs. IT scientists have already developed new tools for other applications, and are flexible to tackle practical problems. For the IT community, the major benefit will be an advancement in their specific modeling tools, identifying new targets, whilst promoting novel solutions for some of the (Q)SAR issues.
The project is performed with the help of an interdisciplinary team, creating a positive impact on the enhanced career prospects of the younger team participants. An integrated approach towards solving problems at interdisciplinary interfaces is of great importance in nowadays scientific and economic society. This project is intensifying training activities at this interface and strengthen the interdisciplinary network that can lead to providing high-impact, economically competitive research and the training of scientists capable of solving urgent problem in this field.
The strengthening of the international connections is an important impact of this project. Through the collaboration with the University of Trieste we have achieved the access to new knowledge and promote our home institution and country. The project is also important for the education of young scientists.One of the goals of this project was to create an interdisciplinary environment that will deliver added value to the participants compared to carrying out their work in single research groups. The PhD students were trained within the network including groups located at two important European institutions in Slovenia and Italy. Through this training, the younger participants acquired stronger and more diverse career opportunities, in particular by getting to interact at the academia-industry interface.
As an indicator of the relevance of the presented research is the recently approved "Inter-reg" project TRANS2CARE (funding provided in 2011) in which we will together with many Italian and Slovenian partners continue the research of trans-membrane proteins in different directions - from theoretical structural research to medicinal applications.
Most important scientific results
Annual report
2009,
2010,
2011,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2009,
2010,
2011,
final report,
complete report on dLib.si
