Stefan Klingl

Suche


A3 Structural biology of plant potyvirus and cytomegalovirus effector proteins

Principal investigator
Yves Muller

Mentor
Jutta Eichler

PhD exam: 23.01.2015

Complex structure of CD4D1D2 and gp120 mimetic peptide CD4bs-M

Infection of immune cells by HIV-1 virus is initiated by one specific interaction between the viral envelope protein gp120 with the host cell surface receptor CD4. The binding site of gp120 for the CD4 receptor constitutes a conserved and accessible region in this otherwise very variable and heavily glycosylated protein, thus making it a good point of attack. Molecules capable of functionally and structurally mimicking the binding site of HIV-1 gp120 for CD4 are therefore good candidates for being HIV-1 entry inhibitors. Additionally, they also may work as immunogens for elicitation of virus neutralizing antibodies. Synthetic peptides have been designed, generated and binding to gp120 has been shown.
Goal of this part of the project is the exploration of the structural basis for the functional mimicry of the CD4-binding site of HIV-1 gp120 by the synthetic peptide CD4bs-M. To clarify the question, if these mimetics can adopt conformations that resemble the CD4-binding site of gp120 X-ray crystallography will be used. Recombinant CD4 is purified and crystallized in complex with this mimetic peptide. This structural analysis will provide new insights in these interactions at atomic level and may govern the design of improved synthetic mimetics.

Figure: A Binding site of gp120 bound to CD4 receptor. The binding site consists of three fragments: Residues 365 to 373 shown in red, 424 to 433 shown in yellow, 454 to 460 shown in green. The bound loop of CD4, residues 24 to 65, is shown in blue. Adapted from the structure of Kwong et al. (1998)[1]. B Chemical structure of CD4bs-M. Peptide fragments in red, yellow and green according to A. C Left: Crystal structure of gp120 bound to CD4. Right: Model of CD4bs-M bound to CD4. Binding fragments of gp120 (Adapted from Kwong et al. (1998)[1]) are shown connected via a stylized peptide scaffold. [1] Kwong, P. D., Wyatt, R., Robinson, J., Sweet, R. W., Sodroski, J. and Hendrickson, W. A. (1998). Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature, 393, 648-659. [2] Franke, R.; Hirsch, T.; Overwin, H. & Eichler, J. (2006). Synthetic mimetics of the CD4 binding site of HIV-1 gp120 for the design of immunogens. Angew Chem Int Ed 46, 1253-1255.

 

Publications

 

 

 

Presentations

July 2013 5th Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Towards the structural characterization of the interaction of human PML and CMV IE1
Talk
     
July 2012 4th Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Crystal structure determination of the immediate early 1 protein from rhesus macaque cytomegalovirus
Talk
     
October 2011 First International SFB 796 Conference: Mechanisms of viral host cell manipulations: from plants to humans, Bamberg, Germany
Structural investigation of the viral effector protein IEF from cytomegalovirus
Poster
     
July 2011 3rd Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Structural investigation of the viral effector protein IE1 from cytomegalovirus
Talk and Poster
     
September 2010 2nd Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Crystallization of the effector protein IE1 from human cytomegalovirus
Talk
     
September 2009 First Annual Retreat, Erlangen School of Molecular Communication, Schloss Atzelsberg, Atzelsberg, Germany
Exploration of the structural basis for the functional mimicry of th the CD4 binding site of HIV-1 gp120. On the way to the complex structure of CD4 with a mimetic peptide
Talk