The Epithelial Biochemistry Laboratory

Epithelial Biochemistry Laboratory

Structure/function analysis of Eph-receptor ephrin-ligand interactions and development of inhibitors

Complementing the functional studies, our laboratory has established a collaborative program to elucidate the structure of the EphA3/ephrinA5 complex, as basis for the rational design of drugs that interfere with receptor activation. While we found previously that sub-domain constructs of the receptor or ligand act as specific antagonists, there is considerable scope in the development of small-molecular weight drugs that interfere with EphA3 signalling. In ongoing studies we pursue the crystallisation of Eph/ephrin complexes, evaluate critical binding interfaces on the receptor by random mutagenesis and molecular modeling and develop screening strategies to identify inhibitors of Eph receptor activation. An integrated application of structure-based and random library screening approaches will provide the groundwork for the design of reagents with clinical potential in cancer treatment.

Example for the distribution of potential phenyl binding sites for small-molecular weight drugs on the surface of the EphA3 ligand binding domain obtained from molecular modeling calculations.

People involved in the research:

Collaborators:

Detlef Geleick, LICR Austin Campus
Dimitar Nikolov, Juha Himanen, Memmorial Sloan Kettering Cancer Centre
Prof. Paul Alewood, Centre for Drug Design and Development, IMB
Herbert Treutlein and Jun Zeng, Cytopia Pty. Ltd.
Christelle Souriau, CSIRO Parkville

Publications:
Crystal structure of an Eph receptor-ephrin complex.
Himanen J-P, Rajashankar KR, Lackmann M, Cowan CA, Henkemeyer M, Nikolov DB.
Nature 414: 933-938 (2001). [Medline entry]

Distinct subdomains of the EphA3 receptor mediate ligand binding and receptor dimerization.
Lackmann M, Oates AC, Dottori M, Smith FM, Do C, Power M, Kravets L, Boyd AW.
J Biol Chem. 273:20228-20237 (1998). [Medline entry]