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PDBsum entry 1yoj
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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 structures of active src kinase domain complexes.
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Authors
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C.B.Breitenlechner,
N.A.Kairies,
K.Honold,
S.Scheiblich,
H.Koll,
E.Greiter,
S.Koch,
W.Schäfer,
R.Huber,
R.A.Engh.
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Ref.
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J Mol Biol, 2005,
353,
222-231.
[DOI no: ]
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PubMed id
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Abstract
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c-Src was the first proto-oncoprotein to be identified, and has become the focus
of many drug discovery programs. Src structures of a major inactive form have
shown how the protein kinase is rigidified by several interdomain interactions;
active configurations of Src are generated by release from this
"assembled" or "bundled" form. Despite the importance of Src
as a drug target, there is relatively little structural information available
regarding the presumably more flexible active forms. Here we report three
crystal structures of a dimeric active c-Src kinase domain, in an apo and two
ligand complexed forms, with resolutions ranging from 2.9A to 1.95A. The
structures show how the kinase domain, in the absence of the rigidifying
interdomain interactions of the inactivation state, adopts a more open and
flexible conformation. The ATP site inhibitor CGP77675 binds to the protein
kinase with canonical hinge hydrogen bonds and also to the c-Src specific
threonine 340. In contrast to purvalanol B binding in CDK2, purvalanol A binds
in c-Src with a conformational change in a more open ATP pocket.
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Figure 1.
Figure 1. Chemical structures of inhibitors (a) purvalanol
A and (b) CGP77675 used for co-crystallization.
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Figure 5.
Figure 5. Binding of the pyrrolo-pyrimidine inhibitor
CGP77675 to the kinase domain of Src. (a) Stereo view of the
inhibitor binding pocket with Sim weighted electron density maps
of the refined complex of CGP77675 and the kinase domain of Src
at 2.3 Å resolution (light brown, 2mF[o] -dF[c], contoured
at 1s) and an omit map (dark brown, mF[o] -dF[c], contoured at
2s) prior to building inhibitor into the model. (b) Stereo view
of the inhibitor binding pocket: molecules A and B of the
asymmetric unit have been superimposed. They show the same basic
binding mode; the differences in the 4-hydroxy-piperidine-ethyl
substituent are well defined by electron density maps.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2005,
353,
222-231)
copyright 2005.
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