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PDBsum entry 2zl2
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References listed in PDB file
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Key reference
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Title
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The structural basis for the activation and peptide recognition of bacterial clpp.
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Authors
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D.Y.Kim,
K.K.Kim.
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Ref.
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J Mol Biol, 2008,
379,
760-771.
[DOI no: ]
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PubMed id
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Abstract
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ClpP and its ATPase compartment, ClpX or ClpA, remove misfolded proteins in
cells and are of utmost importance in protein quality control. The ring hexamers
of ClpA or ClpX recognize, unfold, and translocate target substrates into the
degradation chamber of the double-ring tetradecamer of ClpP. The overall
reaction scheme catalyzed by ClpXP or ClpAP has been proposed; however, the
molecular mechanisms associated with substrate recognition and degradation have
not yet been clarified in detail. To investigate these mechanisms, we determined
the crystal structures of ClpP from Helicobacter pylori in complex with product
peptides bound to the active site as well as in the apo state. In the complex
structure, the peptides are zipped with two antiparallel strands of ClpP and
point to the adjacent active site, thus providing structural explanations for
the broad substrate specificity, the product inhibition and the processive
degradation of substrates in the chamber. The structures also suggest that
substrate binding causes local conformational changes around the active site
that ultimately induce the active conformation of ClpP.
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Figure 4.
Fig. 4. Rearrangement of residues in the active site of
HpClpP by substrate binding. The apo-HpClpP and HpClpP/peptide
complex (a) and apo-HpClpP S99A and HpClpP S99A/peptide complex
(b) are overlapped by superposition of C^α traces. The apo form
is green and the complex form is pink. The residues in the
catalytic triad and peptides are represented by stick models.
Possible bonds between Ser99OG (or Ala99CB) and His124NE2, and
those between His124NE1 and Asp173OD are indicated by dashed
lines and their distances are indicated in angstroms. (c) The
C^α traces of six ClpPs near the catalytic triad are
overlapped. Three residues in the catalytic triad are drawn as
stick models. HpClpP and HpClpP/peptide complex are green and
purple, respectively. ClpPs from E. coli, S. pneumoniae, P.
falciparum and M. tuberculosis are brown (PDB accession number
1TYF), blue (1Y7O), orange (2F6I) and yellow (2CBY),
respectively. (d) Structural overlap of HpClpP/peptide complex
(pink) and EcClpP/inhibitor complex (cyan) near the active site.
The residues of the catalytic triad and bound peptide and
inhibitor are labeled and represented by stick models; those
involved in substrate binding are also labeled and represented
by stick models. The possible hydrogen bonds between HpClpP and
peptide or EcClpP and inhibitor are depicted with dashed lines
and their distances are indicated with the angstrom scale.
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Figure 5.
Fig. 5. Peptide binding in the ClpP chamber and the model of
progressive digestion of the substrate by ClpP. (a) The surface
model of the proteolytic chamber of HpClpP with three peptides
(tetra-Ala) bound to active sites. The surface of each subunit
in HpClpP is represented by a different color and the red area
represents the active-site Ser99. Tetrapeptides bound to the
substrate-binding site are represented by gray stick models. (b)
A linear polypeptide, a substrate translocated from ClpX to the
ClpP chamber, is modeled and aligned along the active sites in
the same color schemes and orientations as in (a). Each
tetrapeptide shown in (a) is extended by adding three more amino
acids. The resulting heptapeptides are connected to form a long
linear peptide. The possible cleavage sites are indicated by
cyan arrows. In this binding mode, a heptapeptide could be the
cleavage product since it is almost the same size as the gap
between adjacent active sites in the extended conformation.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2008,
379,
760-771)
copyright 2008.
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