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].
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).
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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