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PDBsum entry 1a06
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References listed in PDB file
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Key reference
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Title
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Structural basis for the autoinhibition of calcium/calmodulin-Dependent protein kinase i.
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Authors
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J.Goldberg,
A.C.Nairn,
J.Kuriyan.
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Ref.
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Cell, 1996,
84,
875-887.
[DOI no: ]
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PubMed id
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Abstract
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The crystal structure of calcium/calmodulin-dependent protein kinase I has been
determined in the autoinhibited form. The C-terminal regulatory region of the
enzyme forms a helix-loop-helix segment that extends across the two domains of
the catalytic core, making multiple inhibitory interactions. Elements of the
first regulatory alpha helix and the loop interfere with the binding site for
peptide substrates, while the loop and the second helix interact with the
ATP-binding domain to induce conformational changes that obstruct the nucleotide
binding pocket. One part of the calmodulin recognition element protrudes away
from the catalytic domain and is potentially available for an initial
interaction with calmodulin. The structure provides a view of an intact
calmodulin target and suggests that substantial structural changes will
accompany kinase activation by calmodulin binding to the regulatory region.
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Figure 1.
Figure 1. Comparison of the Fold of Autoinhibited CaM
Kinase I with cAPK(A) Ribbon drawing of CaM kinase I (CaMKI;
left) and cAPK (right). The structures of autoinhibited CaMKI
and cAPK are drawn with their C-terminal lobes (helical domain
at bottom) in similar orientations. The cAPK structure is
that of [69], with the PKI peptide inhibitor colored orange and
the ATP shown in ball and stick form (entry 1ATP in the
Brookhaven Protein Data Bank). cAPK has its two domains in a
closed conformation whereas the CaMKI active site is opened
by an 18° relative rotation of the domains, with respect to
cAPK. The regulatory C-terminal sequence of CaMKI, containing
the autoinhibitory region, is colored red (residues 285–316).
The ATP-binding glycine-rich loop or P loop (colored green in
both structures; residues 23–36 in CaMKI, 46–59 in cAPK)
covers the ATP molecule in cAPK. In CaMKI, the P loop interacts
with the autoinhibitory region and adopts a distinct
conformation that distorts the ATP-binding site. Two
disordered regions of CaMKI in the crystal structure are
indicated with dotted lines (ten residues, 54–63, not modeled
in the N-terminal domain, and eighteen residues, 164–181, in
the C-terminal domain, are indicated by the corresponding number
of dots). The region of CaM kinase I that is boxed is shown in
detail in (B).(B) Stereo-diagram showing the interaction between
the CaMKI regulatory segment (red, residues 285–316) and the
catalytic core of the enzyme (gray). Selected residues of the
regulatory region are drawn in white, and residues from the
catalytic core are colored blue. Figure prepared using the
programs MOLSCRIPT ([41]) and Raster3D ( [2]).
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Figure 4.
Figure 4. Solvent-Accessible Surface of Autoinhibited
CaMKIThe C-terminal sequence was omitted from the surface
calculation and, instead, is drawn as a red tube (residues
280–316). The side chains of hydrophobic residues (Ala, Cys,
Ile, Leu, Met, Phe, Trp, Tyr, and Val) that are located in the
C-terminal region are drawn in yellow. The autoinhibitory
sequence, defined by truncation mutagenesis ([25 and 65]) and by
this structural study, is drawn in magenta. Figure was generated
using the program GRASP ( [53]).
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The above figures are
reprinted
by permission from Cell Press:
Cell
(1996,
84,
875-887)
copyright 1996.
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