slide1 n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Structural basis for high-affinity HER2 receptor binding by an engineered protein PowerPoint Presentation
Download Presentation
Structural basis for high-affinity HER2 receptor binding by an engineered protein

Loading in 2 Seconds...

play fullscreen
1 / 17

Structural basis for high-affinity HER2 receptor binding by an engineered protein - PowerPoint PPT Presentation


  • 110 Views
  • Uploaded on

PNAS ∣ August 24, 2010 ∣ vol. 107 ∣ no. 34 ∣ 15039 –15044. Structural basis for high-affinity HER2 receptor binding by an engineered protein. Charles Eigenbrot , Mark Ultsch , Anatoly Dubnovitsky , Lars Abrahmsén , and Torleif Härd. Date : 2010.10.11 Speaker : HAN WON SEOK.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Structural basis for high-affinity HER2 receptor binding by an engineered protein' - petula


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
slide1

PNAS ∣ August 24, 2010 ∣ vol. 107 ∣ no. 34 ∣ 15039–15044

Structural basis for high-affinity HER2 receptor binding by an engineered protein

Charles Eigenbrot, Mark Ultsch, Anatoly Dubnovitsky, Lars Abrahmsén, and TorleifHärd

Date : 2010.10.11

Speaker : HAN WON SEOK

slide2

Structural basis for high-affinity HER2 receptor binding by an engineered protein

Abstract

The human epidermal growth factor receptor 2 (HER2) is specifically overexpressedin tumors of several cancers, including an aggressive form of breast cancer. It is therefore a target for both cancer diagnostics and therapy. The 58 amino acid residue ZHER2 affibodymolecule was previously engineered as a high-affinity binder of HER2. Here we determined the structure of ZHER2 in solution and the crystal structure of ZHER2 in complex with the HER2 extracellular domain. ZHER2 binds to a conformational epitope on HER2 that is distant from those recognized by the therapeutic antibodies trastuzumab and pertuzumab. Its small size and lack of interference may provide ZHER2 with advantages for diagnostic use or even for delivery of therapeutic agents to HER2-expressing tumors when trastuzumab or pertuzumab are already employed. Biophysical characterization shows that ZHER2 is thermodynamically stable in the folded state yet undergoing conformational interconversion on a submillisecond time scale. The data suggest that it is the HER2-binding conformation that is formed transiently prior to binding. Still, binding is very strong with a dissociation constant KD=22pM, and perfect conformational homogeneity is therefore not necessarily required in engineered binding proteins. A comparison of the original Z domain scaffold to free and bound ZHER2 structures reveals how high-affinity binding has evolved during selection and affinity maturation and suggests how a compromise between binding surface optimization and stability and dynamics of the unbound state has been reached.

slide3

Cancer target

Structural basis for high-affinity HER2 receptor binding by an engineered protein

staphylococcal protein A, “affibody”

HER2 binding affibody, “ZHER2”

slide5

Structural basis for high-affinity HER2 receptor binding by an engineered protein

1. Why using Affibody, instead of Ig-antibody for target

2. How engineering high-affinity affibody for target

3. What knowing from ZHER2-HER2 complex structure

slide6

Structural basis for high-affinity HER2 receptor binding by an engineered protein

1. Why using Affibody, instead of Ig-antibody for target

2. How engineering high-affinity affibody for target

3. What knowing from ZHER2-HER2 complex structure

Staphylococcus aureus (포도상구균 )Resisting Opsonization via Protein A

Doc Kaiser's Microbiology Home Page

The Fc portion of the antibody IgG, the portion that would normally binds to Fc receptors on phagocytes, instead binds to protein A on Staphylococcus aureus. In this way the bacterium becomes coated with a protective coat of antibodies that do not allow for opsonization.

slide7

Structural basis for high-affinity HER2 receptor binding by an engineered protein

1. Why using Affibody, instead of Ig-antibody for target

2. How engineering high-affinity affibody for target

3. What knowing from ZHER2-HER2 complex structure

slide8

Structural basis for high-affinity HER2 receptor binding by an engineered protein

1. Why using Affibody, instead of Ig-antibody for target

2. How engineering high-affinity affibody for target

3. What knowing from ZHER2-HER2 complex structure

KD = 22pM

Nature447, 741-744 (7 June 2007)

KD = 0.1nM

slide9

Structural basis for high-affinity HER2 receptor binding by an engineered protein

1. Why using Affibody, instead of Ig-antibody for target

2. How engineering high-affinity affibody for target

3. What knowing from ZHER2-HER2 complex structure

slide10

Structural basis for high-affinity HER2 receptor binding by an engineered protein

1. Why using Affibody, instead of Ig-antibody for target

2. How engineering high-affinity affibody for target

3. What knowing from ZHER2-HER2 complex structure

Expert Opin. Biol. Ther. (2007) 7(4):555-568

slide11

Structural basis for high-affinity HER2 receptor binding by an engineered protein

1. Why using Affibody, instead of Ig-antibody for target

2. How engineering high-affinity affibody for target

3. What knowing from ZHER2-HER2 complex structure

Journal of Biotechnology 140 (2009) 254–269

slide12

Structural basis for high-affinity HER2 receptor binding by an engineered protein

1. Why using Affibody, instead of Ig-antibody for target

2. How engineering high-affinity affibody for target

3. What knowing from ZHER2-HER2 complex structure

Journal of Biotechnology 140 (2009) 254–269

slide13

Structural basis for high-affinity HER2 receptor binding by an engineered protein

1. Why using Affibody, instead of Ig-antibody for target

2. How engineering high-affinity affibody for target

3. What knowing from ZHER2-HER2 complex structure

In the previous study,

Not compete with other antibodies

Not have biological effects

slide14

Structural basis for high-affinity HER2 receptor binding by an engineered protein

1. Why using Affibody, instead of Ig-antibody for target

2. How engineering high-affinity affibody for target

3. What knowing from ZHER2-HER2 complex structure

slide15

Structural basis for high-affinity HER2 receptor binding by an engineered protein

Conclusion

1. Zher2 does not compete with commercial antibodies

2. Zher2 does not have biological effects

3. Zher2 allows for molecular imaging of HER2 without interfering with ongoing therapy using commercial antibodies

4. Zher2 may be used as a carrier of other therapeutic agents to HER2 target

slide17

Structural basis for high-affinity HER2 receptor binding by an engineered protein

References

Thank you