Activin and Bone morphogenetic protein 4 (BMP4) are members of the TGFbeta family of growth factors. They play a vital role in the early embryonic development in vertebrates and are responsible for the development of mesodermal structures in the embryo.
These growth factors signal through two the type I and type II receptors, which both contain a single snake-toxin related domain in their extracellular part. A single dimeric growth factor binds two of each receptors forming a 1:2:2 complex.
There are also several protein inhibitors that can inactivate these growth factors by binding them and preventing interactions with receptors. These inhibitors include follistatin, noggin and chordin, among others.
We are studying the activins, nodals and BMPs and their interacting proteins using biochemical and biophysical methods and try to solve crystal structures of various complexes. By doing this we aim to understand the mechanism by which the signalling is transduced, and the determinants of signalling specificity. Furthermore, we would like to understand how different, structurally unrelated interacting proteins can interact with these growth factors and modulate signalling.
In this large collaboration we are establishing fragment based drug discovery methods from library handling, screening, biophysical characterisation and structural biology through to chemical synthesis of new compounds. We are targeting a traditionally difficult class of drug targets, namely protein-protein interactions. These are challenging targets as typical interaction site is large and relatively flat, lacking the three dimensional features associated with enzyme active sites and other small molecules binding sites typically targeted by drug developers. One of the key challenges we face in this area is to keep the size of the inhibitor small while achieving high potency.
We use a number of complementary biophysical techniques both to screen the fragment libraries and to validate the fragments that have been identified in the initial screen. Structural biology is a key to fragment based approach and we make extensive use of X-ray crystallography to analyse the molecular details of the fragment-protein complexes to guide computational and synthetic design of higher potency chemicals.
As a model system we are targeting the interaction between human recombinase RAD51 and breast cancer associated proteins BRCA2. This interaction is essential for homologous recombination in humans and mutations affecting this predispose people to breast and other cancers. Inhibition of this pathway can lead to more effective therapies for the treatment of various other cancers too.
Cyr61, CTGF and nov are members of the CCN family of modular growth factors. They are made of insulin-like growth factor binding domain (IB), von Willebrand factor C domain (vWC), thrombospondin module 1 ( TSP1) and C-terminal cystine-knot domain (CTCK). Our efforts are focusing on determining three dimensional structures of these modules either in isolation, or preferably, in the context of the full-length protein.
Structural information is available for the N-terminal half of the insulin-like growth factor binding domain from IGBP-1, the TSP1 and vWC domains, but these are all from unrelated proteins, and so far no structural inforamtion is available for the CCN family. Structural studies on CCN family members will not only help us understand these proteins, but also many others with similar domains.