Ernest Laue - Overview
Our interests lie in the study of the structure and
function of macromolecules. We are studying three related areas that link
growth factor and cytokine mediated signalling, to changes in gene expression:
- small GTPase proteins, which control signal transduction pathways,
- cyclin-dependent kinases and their control and
- the control of gene
expression via chromatin structure. At the same time we are developing
new NMR methods to extend the scope of NMR spectroscopy, for the study
of the structure of larger macromolecules and their interactions.
We are currently studying the interactions of the Rho-family GTPases with
their downstream effectors. We have determined the structures of complexes
of Cdc42 with the Cdc42-binding domains from the ACK and PAK kinases and
we are using site-directed mutagenesis and scintillation proximity assays,
as well as further structural studies, to understand how Cdc42/Rac activate
downstream effectors.
Our second major project involves studies of the INK4 family of cyclin-dependent
kinase inhibitors and their interactions with D-type cyclin/CDK complexes.
We have recently determined the crystal structure of the p19/Cdk6 complex,
providing the first insights into how the INK4 class of CDK inhibitors
work. Current work is focussed on determining structures and studying
the interactions of Cdk6 in higher order complexes with cyclins, chaperones
and substrates.
Finally, recent work suggests that changes in the structure of chromatin
often play a crucial role in gene activation. In the last two years it
has become clear that histone methylation plays an important role in the
regulation of chromatin structure and thus gene expression, development,
cellular proliferation and differentiation. Methylation at lysine 9 of
histone H3 (by the Suv39 methyltransferase and its relatives) strongly
correlates with a repressed chromatin state. This repression requires
the recognition of methylated lysine 9 by the MOD1, whose chromodomain
specifically recognizes histone H3 when methylated at lysine 9. Structural
studies, with Dr T. Kouzarides (Wellcome/Cancer Research UK Institute, Cambridge), are
underway.
We are increasingly directing our research towards structural studies
that might be usefully employed in developing new therapies for cancer.
We are presently studying what we feel will be the most appropriate targets
in the p53 and Rb biochemical pathways, which appear to be very often
disrupted in tumour cells. We plan to extend this work to studies of pathways
that are involved in metastasis and invasion. We are particularly interested
in fundamental studies of protein-protein interactions, and in providing
greater understanding and knowledge of how such interactions might be
inhibited – many targets in intra-cellular signalling involve such interactions
and traditionally they have been very difficult to target. In addition
to structural studies we have been developing expertise in the technologies
required for finding, validating and providing lead information for targets
in cancer. We are presently co-ordinating a research programme under the
EU’s Framework Programme 5 in this area.
