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PDBsum entry 1stc
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Complex (transferase/inhibitor)
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PDB id
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1stc
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Staurosporine-Induced conformational changes of camp-Dependent protein kinase catalytic subunit explain inhibitory potential.
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Authors
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L.Prade,
R.A.Engh,
A.Girod,
V.Kinzel,
R.Huber,
D.Bossemeyer.
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Ref.
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Structure, 1997,
5,
1627-1637.
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PubMed id
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Abstract
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BACKGROUND: Staurosporine inhibits most protein kinases at low nanomolar
concentrations. As most tyrosine kinases, along with many serine/threonine
kinases, are either proto oncoproteins or are involved in oncogenic signaling,
the development of protein kinase inhibitors is a primary goal of cancer
research. Staurosporine and many of its derivatives have significant biological
effects, and are being tested as anticancer drugs. To understand in atomic
detail the mode of inhibition and the parameters of high-affinity binding of
staurosporine to protein kinases, the molecule was cocrystallized with the
catalytic subunit of cAMP-dependent protein kinase. RESULTS: The crystal
structure of the protein kinase catalytic subunit with staurosporine bound to
the adenosine pocket shows considerable induced-fit rearrangement of the enzyme
and a unique open conformation. The inhibitor mimics several aspects of
adenosine binding, including both polar and nonpolar interactions with enzyme
residues, and induces conformational changes of neighboring enzyme residues.
CONCLUSIONS: The results explain the high inhibitory potency of staurosporine,
and also illustrate the flexibility of the protein kinase active site. The
structure, therefore, is not only useful for the design of improved anticancer
therapeutics and signaling drugs, but also provides a deeper understanding of
the conformational flexibility of the protein kinase.
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Secondary reference #1
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Title
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Crystal structures of catalytic subunit of camp-Dependent protein kinase in complex with isoquinolinesulfonyl protein kinase inhibitors h7, H8, And h89. Structural implications for selectivity.
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Authors
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R.A.Engh,
A.Girod,
V.Kinzel,
R.Huber,
D.Bossemeyer.
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Ref.
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J Biol Chem, 1996,
271,
26157-26164.
[DOI no: ]
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PubMed id
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Figure 4.
Fig. 4. A, spatial structures of H inhibitors and MnAMP-PNP.
Molecules as stick model, the bromine of H89 is shown as CPK
model. Atom colors: white, carbon; blue, nitrogen; red, oxygen;
yellow, sulfur; purple, bromine and manganese. B, congruence of
H8 (yellow carbon atoms) and adenosine (white carbon atoms)
after superposition of H8-cAPK·PKI and AMPPNP-cAPK·PKI.
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Figure 9.
Fig. 9. Stereo picture of H7 bound to the active site of the
kinase. Hydrogen bonds are depicted in dotted lines.
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The above figures are
reproduced from the cited reference
with permission from the ASBMB
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Secondary reference #2
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Title
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Phosphotransferase and substrate binding mechanism of the camp-Dependent protein kinase catalytic subunit from porcine heart as deduced from the 2.0 a structure of the complex with mn2+ adenylyl imidodiphosphate and inhibitor peptide pki(5-24).
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Authors
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D.Bossemeyer,
R.A.Engh,
V.Kinzel,
H.Ponstingl,
R.Huber.
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Ref.
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Embo J, 1993,
12,
849-859.
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PubMed id
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Secondary reference #3
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Title
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A new alkaloid am-2282 of streptomyces origin. Taxonomy, Fermentation, Isolation and preliminary characterization.
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Authors
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S.Omura,
Y.Iwai,
A.Hirano,
A.Nakagawa,
J.Awaya,
H.Tsuchya,
Y.Takahashi,
R.Masuma.
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Ref.
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J Antibiot (tokyo), 1977,
30,
275-282.
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PubMed id
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