Anna Kahler

Suche


A2 Computational analysis of linear interaction motifs and globular protein interfaces in effector proteins

Principal investigator
Heinrich Sticht

Mentor
Nuska Tschammer

Investigation of the structure and dynamics of heterodimeric viral GPCRs

Several viruses express GPCRs that interfere efficiently with the signalling pathways of their host. We want to investigate the molecular mechanisms that lead to functional selectivity as a result of receptor heterodimerization; in this context, we want to model heterodimers of pUS27 and pUS28, as well as heterodimers with cellular receptors. There will be a particular focus on the interaction with cellular CXCR4, because this receptor has been previously shown to be a target for heterodimer formation with viral receptors. Modeling of the respective complexes is based on the crystal structure of homodimeric CXCR4 and the fact that both US27 and US28 share a sequence identity of approximately 30-40% with CXCR4. Initial simulations will be performed for the CXCR4 homodimer, which will allow us to validate our simulation approach based on the experimental dimer structure available. Subsequent structural analysis will be performed to assess the role of individual residues for dimer formation. Afterwards, we intend to investigate the CXCR4-US27, CXCR4-US28, US27-US28 heterodimers and US28 homodimers to assess their conformational stability. In case of stable associations, suggestions for mutations will be made that will be experimentally tested. Further simulations are planned for those cellular receptors that will be identified as novel candidates for heterodimer formation with US27/US28 from the experimental work.

Figure: Dimerization of human and viral GPCRs.Initial simulations will be performed for the CXCR4 homodimer (1). Afterwards, we intend to investigate the CXCR4-US27 and CXCR4-US28 heterodimers (2), US27-US28 heterodimers (3) and US27 and US28 homodimers (4) to assess their conformational stability.

 

Publications

Kahler, A., Horn, A.H.C. and Sticht, H. (2015). A computational Study of the Structure and Dynamics of the E. coli Transcription Factor RfaH. Curr Biotechnol 4(1): 26-38.

Horn, A.H.C. and Kahler, A. (2013). The effect of fulvic acid on pre- and postaggregation state of Aβ17-42: molecular dynamics simulation studies, S. Verma, A. Singh and A. Mishra, Biochim Biophys Acta 1834 (2013) 24-33. Biochim Biophys Acta - Proteins and Proteomics 1834(12): 2867-2868.

Kahler, A., Sticht, H. and Horn, A.H.C. (2013). Conformational Stability of Fibrillar Amyloid-Beta Oligomers via Protofilament Pair Formation - A Systematic Computational Study. PLoS ONE 8(7): e70521.

Kahler, A., Horn, A.H.C. and Sticht, H. (2013). Stability of single and double layer fibrillar amyloid-β oligomers. J Cheminform 5(Suppl 1):P9.

 

Presentations

October 2015 2nd International SFB 796 Conference: Mechanisms of microbial host cell manipulation: From plants to humans, Erlangen, Germany
”Homology modeling of the viral GPCR US27”
Poster
     
July 2015

Research Day of the Emil Fischer School, Erlangen, Germany
”Homology modeling of the viral GPCR US27”

Poster
     
July 2015 7th Annual Retreat, Erlangen School of Molecular Communication, Schloss Hirschberg, Beilngries, Germany
”Homology modeling of vGPCR US27 ”
Talk
     
April 2015 Workshop on Computer Simulation and Theory of Macromolecules, Hünfeld, Germany
Dynamics of the autoinhibited transcription factor RfaH
Poster
     
March 2015 29th Molecular Modelling Workshop 2013, Erlangen, Germany
Dynamics of the autoinhibited transcription factor RfaH
Poster
     
July 2014 6th Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
"Putative Dimerization Interfaces of viral GPCRs"
Poster
     
April 2014 Workshop on Computer Simulation and Theory of Macromolecules, Hünfeld, Germany
Putative Dimerization Interfaces of viral GPCRs
Poster
     
March 2014 28th Molecular Modelling Workshop 2013, Erlangen, Germany
Conformational stability and oligomerization properties of the viral GCPRs US27 and US28
Poster
     
July 2013 5th Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Computational investigation of putative dimerization interfaces of HCMV GPCRs
Talk
     
July 2013 Research Day of the Emil Fischer School, Erlangen, Germany
Conformational Switches of Protein Domains: The Key to RfaH Function
Poster
     
April 2013 Hünfeld 2013 Workshop on Computer Simulation and Theory of Macromolecules, Hünfeld, Germany
Stability of Fibrillar Aβ-Oligomers: Unraveling the Growth Mechanism of Aβ-Fibrils
Talk
     
April 2013 Hünfeld 2013 Workshop on Computer Simulation and Theory of Macromolecules,Hünfeld, Germany
Conformational Switches of Protein Domains: The Key to RfaH Function
Poster
     
February 2013 27th Molecular Modelling Workshop 2013, Erlangen, Germany
Local Tuning of the Conformational Flexibility of RfaH
Poster
     
November 2012 8th German Conference on Chemoinformatics, Goslar, Germany
Stability of Single and Double Layer Fibrillar Amyloid-β Oligomers
Poster
     
July 2012 Bayreuther Strukturtage 2012, Thurnau, Germany
RfaH: A Closer Look at the Conformational Dynamics underlying its Function
Poster
     
July 2012 Research Day, Emil Fischer School, Erlangen, Germany
Influence of Double Layer Formation upon Fibrillar Aβ-Oligomers
Poster
     
April 2012 Hünfeld 2012 Workshop on Computer Simulation and Theory of Macromolecules, Hünfeld, Germany
Influence of Double Layer Formation upon Fibrillar Aβ-Oligomers
Poster
     
March 2012 26th Molecular Modelling Workshop 2012, Erlangen, Germany
How Quartenary Structure Influences the Conformation of Fibrillar Aβ-Oligomers
Poster
     

Awards

Best Talk Award

second place

7th Annual Retreat, Erlangen School of Molecular Communication, Schloss Hirschberg, Beilngries, Germany, July 2015
"Homology modeling of vGPCR US27"