National Cancer Research Institute South of England
Prostate Cancer Collaborative
Research

Engineering NK1 as a MET antagonist for cancer therapy

Authors
Dr Ermanno Gherardi
University of Cambridge

Synopsis

There is considerable evidence, both pre-clinical and clinical, involving the growth factor HGF/SF and its receptor MET [1,2] in invasion and metatasis of prostatic carcinoma cells. There is also proof of concept that fragments of HGF/SF that behave as partial MET antagonist   can abolish in vitro invasion of prostatic carcinoma cells. The aim of this project is to engineer fragments of the polypeptide growth factor HGF/SF, such as NK1, as receptor antagonists for cancer therapy. The work builds on on the structure and mechanism of activity of NK1, the receptor binding fragment of HGF/SF.

The crystal structure of NK1 shows a head to tail dimer with an extensive interprotomeric surface (Fig. 1) [3].

Figure 1.

NK1 requires heparan sulphate for activity and the same dimer is found in crystal structures of NK1-heparin complexes [4]. Heparin binds predominantly to the N-domain but also makes several contacts with the K1 domain (Fig. 2).

Figure 2

For engineering NK1 as a MET antagonists we are following several strategies. The first of these involves re-engineering of the linker connecting the N and K1 domain because the linker plays an important role in the packing of the NK1 dimer and may control the formation of the NK1 dimer itself via domain swapping [5].   Additional approaches are also explored which rely on engineering fragments of HGF/SF containing combinations of kringle domains but lacking the N domain.

References

[1]  Cooper , C.S., Park, M., Blair, D.G.,et al., (1984) Nature 311 , 29-33.

[2]  Bottaro, D.P., Rubin, J.S., Faletto, D.L., et al. (1991) Science 251 , 802-4.

[3]  Chirgadze, D. Y., Hepple, J. P., Zhou, H., et al (1999). Nat Struct Biol 6 , 72-9

[4]  Lietha, D., Chirgadze, D.Y., Mulloy, B., et al.   (2001). Eur Mol Biol Org J 20 , 5543-55.

[5]  Watanabe,   K., Chirgadze,    D.Y., Lietha , D., et al., J mol Biol   319 , 283-288 (2002)

 

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