1 Max-Planck-Institute of Molecular Physiology, Department Structural
Biology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
The Rho GTPases
constitute a large family of small GTP binding proteins that control diverse
cellular functions like the actin cytoskeleton, cell polarity, gene expression,
microtubule dynamics and vesicular trafficking [1]. The understanding of their
function at molecular level belongs therefore to the important tasks of
molecular biology. Second reason why Rho GTPases attract the attention of
scientists is that their abnormal activation plays a role in tumour invasion
and metastasis [2] and in a diseases like the hypertension or bronchial asthma
[3].
We will present
the results of molecular modelling methods applied to some particular problems
concerning Rho GTPases. First we will discuss the model of RhoA cycle at atomic
level constructed on the base of known crystal structures of corresponding sub-states
of the cycle. Then we will demonstrate the importance of global dynamics of
proteins in their function that emerged from the functional analysis of
different Rac1 isoforms [4]. Finally we will report the outcomes from the in-silico
virtual screening focused in this case on the modifications of nucleotides that
would increase their affinities towards the Cdc42 and the compounds capable to
abolish the interaction of RhoA with its effector protein ROCKI and the
interaction of Rac1 with its guanine nucleotide exchange factor Tiam1.
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Jaffe & A. Hall, Adv. Cancer Res.
84 (2002), 57-80.
3. N.
Wettschureck & S. Offermanns, J. Mol. Med. 80 (2002), 629-638.
4. L. C.
Haeusler, L. Blumenstein, R. Dvorsky & M. R. Ahmadian, FEBS
Lett. 555 (2003), 556-560.