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CAM833
The very first biochemically, biophysically,
structurally and mechanistically validated
inhibitor of the protein-protein interaction
between RAD51 and BRCA2.
CAM833 inhibits binding of BRC4 repeats to
RAD51 and the self-association of RAD51. It
blocks formation of RAD51 foci and filaments,
preventing DNA repair, potentiates cytotoxicity
by IR and synergises with PARP1 inhibitors
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Allegedly allosteric CK2α inhibitors are
ATP competitive
Here, we report analysis of a series of inibitors that were
published recently as binding to allosteric site on CK2α
kinase. Prompted by chemoinformatic analysis, we use
X-ray crystallography, ligand-based NMR, HDX-MS and
ITC to show that these molecules bind in fact to the ATP
site and are competed by CX4945, well validated CK2α
inhibitor
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In this study, we set out to structurally characterise
the precursor form of myostatin, a key negative regulator
of muscle mass in animals and attractive therapeutic target
for the treatment of muscle wasting diseases. Here we report
a 2.6 Å crystal structure of human pro-myostatin, which
alongside biophysical and functional analysis, provides a
molecular basis for the controlled activation of growth factor
signalling.
Structure of human pro-myostatin
In this study, we set out to structurally characterise
the precursor form of myostatin, a key negative
regulator of muscle mass in animals and attractive
therapeutic target for the treatment of muscle
wasting diseases.
Here we report a 2.6 Å crystal structure of human
pro-myostatin, which alongside biophysical and
functional analysis, provides a molecular basis
for the controlled activation of growth factor signalling.
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vWC domain from collagen 2A and CCN3
von Willebrand factor C domains are small extracellular domains found in
tens of proteins in human genome. Both CCN3 and Col2A vWCs
are thought to bind to BMP2, and the aim for Emily
and Emma was to test this using purified proteins.
They were able demonstrate that Col2A binds weakly to BMP2,
using novel epitope for this, whereas CCN3 vWC shows no detectable
binding to this proposed ligand.
And by solving crystal structures of both domains, their structural
properties could be characterised.
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CAM4066. The most specific CK2alpha inhibitor to date
Paul identified, using high concentration soaking, a novel pocket
just underneath the ATP binging site in CK2a, the most
promiscuous of kinase in human. This αD pocket pocket,
revealed by a displacement of a helix, has never been seen
before and it allowed us, togther with chemists from the
active site of the kinase.
The resulting molecule, CAM4066, binds to the
kinase with 300 nM affinity and has been shown
to be the most specfic inhibitor of this kinase today.
We are the Hyvönen Research Group at the Department of Biochemistry, University of Cambridge, led by Marko.
Our research is aiming to understand how proteins function, how signals are transmitted from one cell to another, how We use various biochemical, biophysical and structural biology methods to study our target proteins and their interacting partners, to reveal determinants of affinity and specificity of these interactions at atomic level detail.
One of our main focus is on the TGF-β family growth factors, their receptors and interacting proteins.We are trying to understand how these growth factors are regulated in the extracellular space, how they are activated from their precursor state and how they interact with their regulators such as follistatin and gremlin.
We are also developing tools, small molecules, peptides and proteins, that can modulate these processes.We use fragment-based drug discovery approaches to find initial hits that serve as starting points for the inhibitor development. By using serial protein crystallography and biophysical analyses, we support the structure-guided design efforts with our collaborators.
We are very collaborative and support many of our colleagues’ research with structural biology, helping them to produce high quality proteins, to analyse their interactions and to determine structures of these proteins and theor compelxes by X-ray crystallography.
We are funded by Wellcome Trust, Rosetrees Trust, BBSRC and by collaborators in academia and industry.



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