Scientific Program

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Scientific Program Day 1
Scientific Program Day 2

Day 1 :

Keynote Forum

Annette G Beck-Sickinger

Leipzig University, Germany

Keynote: Structural insights in the binding mode of neuropeptide Y at G protein coupled receptors and consequences for drug development
Conference Series Structural Biology Meet 2018 International Conference Keynote Speaker Annette G Beck-Sickinger photo
Biography:

Annette G. Beck-Sickinger studied chemistry and biology at the University of Tubingen (Germany) and received her Ph. D. in organic chemistry.  She was post-doc with E. Carafoli (Laboratory of Biochemistry, ETH Zurich) and appointed as assistant professor of Pharmaceutical Biochemistry at ETH Zurich. Since October 1999, she is full professor of Biochemistry and Bioorganic Chemistry at the University of Leipzig. She spent a sabbatical at Vanderbilt University (Nashville, TN) as visiting professor. Annette Beck-Sickinger was a member of the Board of the German Chemical Society (Gesellschaft Deutscher Chemiker, 2004-2012; Vice-President 2006-2008) and of the DFG panel "Biochemistry“ (2004-2012). Since 2017 she is member of the Board of the German Society for Biochemistry and Molecular Biology (gbm) and Vice-President. She has been awarded protein-coupledmany prices including the Leonidas Zervas Award of the European Peptide Society, the gold medal of the Max-Bergmann-Kreis (2009), the Leipzig Science Award (2016) and the Albrecht Kossel Award of the GDCh (2018). She was honoured with the membership of the Saxonian Academy of Science in 2009 and in 2012, she became an elected member of the German National Academy of Sciences Leopoldina. In 2017, she was awarded cross-linkingthe Saxonian Order of Merit. Her major reseach fields are structure-activity-relationships of peptide hormones and G protein coupled receptors and protein modification to study function and interaction. A tight connection of chemical methods, bioorganic synthesis and molecular biology tools, including cloning, receptor mutagenesis, protein expression and cell biochemistry is applied. Her interests include identification of novel targets and novel therapeutic concepts and novel approaches to modify proteins and concepts for improved enzyme catalysis and biomaterials.

 

Abstract:

Peptides hormones play an important role in the regulation of manifold activities in the body. Many of them transmit their activity through G-Protein Coupled Receptors (GPCR), which are among the most promising drug targets nowadays. Accordingly, elucidating the binding mode of ligands is essential. Whereas several small molecule systems have been well characterized, ligand binding of large and flexible peptides is still more challenging. In addition to ligand binding and receptor activation, indirect mechanisms have been shown to play a role for drugs addressing GPCRs. This includes desensitization, internalization and accordingly their potential use as drug shuttles, e.g. in tumor targeting. Accordingly, in addition to ligand binding, internalization has to be addressed and to be studied, including arrestin recruitment. Accordingly, ligand binding, structural dynamics, and internalization have to be addressed and to be studied to address G protein-coupled receptors for drug development. The neuropeptide Y/pancreatic polypeptide family contains 36 amino acid peptides that bind in human to four different so-called Y-receptors. By a combination of X-ray analysis, NMR, molecular modeling and cross-linking combined with mass spectrometry, we could recently identify the distinct binding modes of NPY to the Y1- and the Y2 receptors. We could further demonstrate that chemical modification of the ligand, including fluorescence labeling, lipidization, and PEGylation significantly modifies the trafficking of the ligand. By labeling of the receptor with a novel template-assisted ligation strategy, we can follow ligand/receptor complexes in living cells. Furthermore, we identified a different mode of arrestin binding and recruitment. Neuropeptide Y1 and Y2 receptors have been shown to play a relevant role in different tumors. In breast cancer we demonstrated that human Y1 receptors are addressable by peptide conjugates using 99mTc or 18F PET-tracers. We now designed Y1 receptor selective peptides linked to different toxophors. Furthermore, we characterized the mechanism of direct and peptide-mediated uptake of tubulysin-related toxins. In the field of tumor therapy, peptide-drug conjugates are already well accepted. However, the concept of receptor-mediated internalization and subsequent tissue specific intracellular application is not limited to the selective addressing of tumors. This may open up a new field of targeted therapy by mid-sized drugs.
 

  • 3D Structure Determination| Computational Approaches in Structural Biology| Hybrid Approaches for Structure Prediction| Structural Bioinformatics and Proteomics
Location: Alto
Speaker

Chair

Annette G Beck-Sickinger

Leipzig University

Session Introduction

Ozge Sensoy

Istanbul Medipol University, Turkey

Title: 11:30 - 12:10
Speaker
Biography:

Ozge Sensoy has her research studies focused on understanding molecular mechanisms of biologically important systems and also providing mechanistic insight at the molecular level. She has been working with GPCRs and their interacting partners which are responsible for cellular signaling. She has been awarded an international COST grant which is based on developing heterobivalent molecules capable of binding more than one target for treatment of symptoms of Parkinson’s disease.
 

Abstract:

Parkinson’s disease is caused by disruption of cells which provide dopamine to the striatum in the brain. Therefore, the main approach made for treatment of the disease has based on increasing dopaminergic signaling by using dopamine agonists, preventing dopamine breakdown via monoamine oxidase enzymes or supplying additional dopamine in the form of L-dopa. Even though L-dopa is known as the most effective drug so far, its efficacy decreases with time due to the use of high dosage of the drug. Moreover, it also causes motor complications such as motor fluctuations and dyskinesia. In this multidisciplinary project, we have aimed for developing hetero-bivalent ligands that target A2AR (Adenosine-2A-receptor)-D2R (Dopamine-2receptor) hetero-tetramer, which has been shown to be the dominant stoichiometry of A2AR-D2R. Firstly, we design and dock hetero-bivalent ligands to the receptors and investigate the molecular mechanism of allosteric interactions within the heterotetramer by means of accelerated molecular dynamics simulations. Subsequently, successful drug candidates are synthesized and tested in vitro for their activities. More importantly, the drug candidates are also tested by in silico and in vitro models for their permeation against blood-brain barrier. So far, hetero-bivalent ligands have been only used as molecular tools for detecting the existence of the receptor dimers. On the other hand, the current study will provide a chance to test the capability of hetero-bivalent ligands for being used as therapeutic molecules. In this way, we expect to develop more effective therapeutic molecules to alleviate the symptoms of Parkinson’s disease hence increasing the quality of patient’s life

Ozge Sensoy

Istanbul Medipol University

Title: 11:30 - 12:10
Biography:

Ozge Sensoy has her research studies focused on understanding molecular mechanisms of biologically important systems and also providing mechanistic insight at the molecular level. She has been working with GPCRs and their interacting partners which are responsible for cellular signaling. She has been awarded an international COST grant which is based on developing heterobivalent molecules capable of binding more than one target for treatment of symptoms of Parkinson’s disease.
 

Abstract:

Parkinson’s disease is caused by disruption of cells which provide dopamine to the striatum in the brain. Therefore, the main approach made for treatment of the disease has based on increasing dopaminergic signaling by using dopamine agonists, preventing dopamine breakdown via monoamine oxidase enzymes or supplying additional dopamine in the form of L-dopa. Even though L-dopa is known as the most effective drug so far, its efficacy decreases with time due to the use of high dosage of the drug. Moreover, it also causes motor complications such as motor fluctuations and dyskinesia. In this multidisciplinary project, we have aimed for developing hetero-bivalent ligands that target A2AR (Adenosine-2A-receptor)-D2R (Dopamine-2receptor) hetero-tetramer, which has been shown to be the dominant stoichiometry of A2AR-D2R. Firstly, we design and dock hetero-bivalent ligands to the receptors and investigate the molecular mechanism of allosteric interactions within the heterotetramer by means of accelerated molecular dynamics simulations. Subsequently, successful drug candidates are synthesized and tested in vitro for their activities. More importantly, the drug candidates are also tested by in silico and in vitro models for their permeation against blood-brain barrier. So far, hetero-bivalent ligands have been only used as molecular tools for detecting the existence of the receptor dimers. On the other hand, the current study will provide a chance to test the capability of hetero-bivalent ligands for being used as therapeutic molecules. In this way, we expect to develop more effective therapeutic molecules to alleviate the symptoms of Parkinson’s disease hence increasing the quality of patient’s life

Meriem El Ghachi

University of Liege, Belgium

Title: 12:10 - 12:50
Speaker
Biography:

Meriem El Ghachi has completed her PhD from Paris University of Paris-Sud, France. He is a Post-doctorate at University of Liege, Belgium. She has published 17 papers in reputed journals.

Abstract:

Undecaprenyl-phosphate C55-P is a key lipid carrier of glycan intermediate required for the synthesis of a variety of cell wall polymers such as Peptidoglycan (PG), Lipopolysaccharides (LPS) O-antigen wall teichoic acids, capsular polysaccharide, common enterobacterial antigen, membrane-derivative oligosaccharides and exopolysaccharides. In bacteria, during peptidoglycan synthesis, the phospho-N-acetylmuramoyl (-pentapeptide) -N-acetyl glucosamine is the essential motif carried by the C55-P. The resulting lipid, C55-PP-MurNAc-(pentatpetide)-GlucNAc (lipid II), is translocated towards the periplasmic side by several putative flippases. The MurNAc-(pentatpetide)-GlucNAc is added to the elongating chains of PG and C55- P is released as C55- PP. This precursor is also provided by the de novo synthesis in the cytosol that is catalyzed by a Cis-Prenyl Pyrophosphate Synthase, UPPS, which successively adds eight isoprene units from C5-PP on farnesyl pyrophosphate. Two families of phosphatases can perform the subsequent dephosphorylation of C55-PP into C55-P, common to the in vitro synthesis and carrier lipid recycling. In E. coli, 1 BacA and 3 phosphatidic acid phosphatases 2 (PgpB, YbjG and LpxT), active on C55-PP have been identified. PgpB being also involved in the phosphatidyl glycerol metabolism and LpxT transferring the phosphate from C55-PP to lipid A. Whereas Bacillus subtilis has three C55-PP phosphatases 1 BacA (YubB) and 2 phosphatidic acid phosphatases 2 (YwoA and YodM). We obtained the structure of BacA using lipidic cubic phase method. The crystal structure at 2.6 A revealed an unexpected fold according to the previous biochemical studies. Moreover, we solved the structure of bsPgpB (yodM) in the presence and absence of its favorite substrate, phosphatidyl glycerol. 

Ghazaleh Gharib

Sabanci University Nanotechnology Research and Application Center, Turkey

Title: Cloning, sequencing, purification and characterization of highly thermostable aspartate aminotransferase from Geobacillus thermopakistaniensis
Speaker
Biography:

Ghazaleh Gharib received her Bachelor’s degree in General Biology from Ferdowsi University of Mashhad, Iran in 2004. She completed her MSc in Biotechnology from Institute of Biochemistry and Biotechnology University of the Punjab in 2008 and then completed her PhD in 2016 from School of Biological Sciences, University of the Punjab under HEC scholarship. Her work is majorly focused on study of hyperthermophiles and archaeal enzymes. She is currently pursuing her Postdoctoral research studies on a project approved by TUBITAK International fellowship in Sabanci University Nanotechnology Research and Application Center, Istanbul, Turkey.
 

Abstract:

Aspartate aminotransferase gene consists of 1,182 bp nucleotide encodes for 393 amino acids was sequenced, cloned, expressed and purified to homogeneity. Enzyme exhibited maximum activity at pH 7 at 65 ºC. Mass spectrometry determined molecular mass of 42,562 Da and gel filtration indicated the protein exist as a dimeric form. Thermo stability experiment showed 100% stability of a protein at 65 ºC for 16 hours and half-life of 15 mins at 75 ºC. The thermal denaturation studies by CD spectroscopy showed no significant change in ellipticity of the helical structure of the protein below 70 ºC. Km and Vmax values towards aspartate were 1.61 mM and 97 µmol min-1 mg-1 and towards α-ketoglutarate were 2.5 mM and 50 µmol min-1 mg-1, respectively. Substrate specificity experiment indicated maximum activity with aspartate and its respective keto acid (α-ketoglutarate ) while exhibits 27% of activity with Tyr and 16% of its activity with Pro and Cys and no activity with Glu how ever in reverse reaction of Glutamate with its keto acid, oxaloacetate, 70% of activity was observed. Pyridoxal phosphate quantification exhibited 0.1 mole of PLP per mole of enzyme. Amino acid analysis showed high contents of charged and especially acidic residues of Aspartate and glutamate in structure of ASTSBS enzyme. Homology modeling determined the Dimeric structure of ASTSBS which contained high number of proline on a surface of each sub-units as compare to its mesophilic counter parts that is a reason for stability of a protein at high temperature.
 

Sushil Tripathi

University of Helsinki, Finland

Title: Systematic transcriptomic profiling defines critical LKB1substrates in gastrointestinal tumorigenesis
Speaker
Biography:

Sushil Tripathi is a postdoctoral researcher in University of Helsinki. He had completed his PhD from Norwegian University of Science and Technology, Norway. 

Abstract:

The mechanism by which loss-of-function mutations of the LKB1 kinase lead to Peutz- Jeghers Syndrome (PJS) polyposis is unknown. Based on PJS models the characteristic hamartomatous polyps are driven by clonally expanding stromal myofibroblasts providing a starting point for molecular studies. LKB1 phosphorylates and thereby activates at least 14 related family kinases including AMPKa1, AMPKa2, NUAK1, NUAK2, SIK1, SIK2, SIK3, SNRK, BRSK1, BRSK2, MARK1, MARK2, MARK3 and MARK4. Genetically, LKB1 has been implicated as a regulator of metabolism, polarity, cell growth and migration and the LKB1 substrate kinases are partly linked to these cellular events. However, it is unknown, which of the LKB1 substrates are critical for LKB1-mediated tumor suppression. To investigate this, we established an in vitro system to study molecular changes following shRNA-mediated depletion of Lkb1 substrate kinases in cultured fibroblasts with myofibroblast characteristics. In this system, loss of Lkb1 leads to transcriptomic changes (Lkb1-signature) with a highly significant overlap with changes observed in Lkb1-deficient tumors in vivo, thus allowing for further defining a 134 gene Lkb1-myofibroblast signature possibly involved in driving tumorigenesis. Gene Set Enrichment Analysis (GSEA) of Lkb1- myofibroblast signature genes indicates that the Lkb1-deficiency is associated with signatures of Cancer-Associated Fibroblasts (CAFs) and extracellular matrix organization. Depletion of 14 Lkb1 substrate kinases lead to variable overlaps with Lkb1-signature genes and cumulatively the overlap is 75% supporting their importance in mediating Lkb1 functions. We have validated some these substrates and their commonly regulated genes for their involvement as potential mediators of tumorigenesis.
 

Maryam Alobathani

University of Sharjah, UAE

Title: Prevalence of Non-syndromic hearing loss in UAE due to genetic mutation in Mitochondrial 12S rRNA
Speaker
Biography:

Maryam Alobathani has completed her Bachelor studies in Biotechnology by age 22 from University of Sharjah and know she’s working as a laboratory supervisor and completing her Master studies at the same university.

 

Abstract:

Deafness is a disease of inability to hear referred as hear impairment or anacusis for those with low or no hearing. It’s important at all levels of health care due to their significant burden on affected individuals and societies. Hearing loss can be classified as partial or completely inability to hear. Deafness can occur due to different mutations in different human genome such as Connexin26 the most common deafness gene, CDH23, TMC1 and in mitochondria. mitochondrial organelle is ubiquitous in eukaryotic as intracellular double membrane structure. The main function of mitochondria is to synthesis ATP by OXPHS and plays important roles in cell death and oxidative stress control. Mutation in mitochondrial DNA cause OXPHS defects that leads to many diseases one of them is hearing loss as syndromic and non-syndromic deafness. Therefore, we aim in this research to identify the genetic causes of NSAHL underlying wide spectrum of congenital conditions in UAE population. This study focused on a non-syndromic deafness caused by mutation on a mitochondrial MTRNR1 gene that encodes 12SrRNA. 40 Samples were collected from unrelated NSHL UAE family members and screened using biological tools such as PCR, Genomic sequencing machines and Bioinformatics tools. Expert geneticist recruiting and clinically assessing the participant patients involved in this study.The main approaches proposed are: (i) homozygosity maps were used to localize the homozygous regions in each particular family, (ii) next generation sequencing platform used to sequence the whole-exome of an affected individuals to explore all variants including the pathogenic mutations, finally (iii) pathogenicity of the outcoming variant results validated or ruled out by performing functional assays. The study indicates two out of the total 40 samples of unrelated UAE families with deafness due to mitochondrial 12S rRNA mutation m.669 T>C and m.827A>G, as well some known polymorphisms. This study is part of other researches done on a larger scale on similar area of interest that will reach to figure out new mutation related to mtDNA 12S rRNA variations. This finding can also help in future genetic counselling, prenatal screening, and post-natal genetic diagnosis to prevent the prevalence of more NSHL patients.