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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 Dr. Marko Hyvönen.
Our research is aiming to understand how cells in humans communicate with each other, how signals are transmitted from one cell to another, how these transmissions are regulated and how cells interpret these signals at atomic level detail. Our main focus is on the TGF-beta family growth factors and their receptors and interacting proteins. We also collaborate extensively with groups in Cambridge and beyond, especially in structure-guided drug discovery projects.
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.
Many disease states are affects by errors in communication between and within cells, and we hope to elucidate these details in order to understand how complex organisms work and what causes these diseases. Using this information we use methods like fragment-based ligand discovery to develop chemical tools that modulate these signalling molecules and help to study their biology. Some of these will also serve as starting points for the development of novel therapeutics.
