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PDBsum entry 3wbl
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Transferase/transferase inhibitor
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PDB id
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3wbl
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References listed in PDB file
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Key reference
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Title
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Crystal structure of human cyclin-Dependent kinase-2 complex with mk2 inhibitor tei-I01800: insight into the selectivity.
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Authors
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A.Fujino,
K.Fukushima,
T.Kubota,
T.Kosugi,
M.Takimoto-Kamimura.
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Ref.
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J Synchrotron Radiat, 2013,
20,
905-909.
[DOI no: ]
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PubMed id
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Abstract
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Mitogen-activated protein kinase-activated protein kinase 2 (MK2 or MAPKAP-K2)
is a Ser/Thr kinase from the p38 mitogen-activated protein kinase signalling
pathway and plays an important role in inflammatory diseases. The crystal
structure of the MK2-TEI-I01800 complex has been reported; its Gly-rich loop was
found to form an α-helix, not a β-sheet as has been observed for other Ser/Thr
kinases. TEI-I01800 is 177-fold selective against MK2 compared with CDK2; in
order to understand the inhibitory mechanism of TEI-I01800, the cyclin-dependent
kinase 2 (CDK2) complex structure with TEI-I01800 was determined at 2.0 Å
resolution. Interestingly, the Gly-rich loop of CDK2 formed a β-sheet that was
different from that of MK2. In MK2, TEI-I01800 changed the secondary structure
of the Gly-rich loop from a β-sheet to an α-helix by collision between Leu70
and a p-ethoxyphenyl group at the 7-position and bound to MK2. However, for
CDK2, TEI-I01800 bound to CDK2 without this structural change and lost the
interaction with the substituent at the 7-position. In summary, the results of
this study suggest that the reason for the selectivity of TEI-I01800 is the
favourable conformation of TEI-I01800 itself, making it suitable for binding to
the α-form MK2.
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