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PDBsum entry 2bug
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References listed in PDB file
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Key reference
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Title
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Conformational diversity in the tpr domain-Mediated interaction of protein phosphatase 5 with hsp90.
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Authors
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M.J.Cliff,
R.Harris,
D.Barford,
J.E.Ladbury,
M.A.Williams.
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Ref.
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Structure, 2006,
14,
415-426.
[DOI no: ]
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PubMed id
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Abstract
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Protein phosphatase 5 (Ppp5) is one of several proteins that bind to the Hsp90
chaperone via a tetratricopeptide repeat (TPR) domain. We report the solution
structure of a complex of the TPR domain of Ppp5 with the C-terminal
pentapeptide of Hsp90. This structure has the "two-carboxylate clamp" mechanism
of peptide binding first seen in the Hop-TPR domain complexes with Hsp90 and
Hsp70 peptides. However, NMR data reveal that the Ppp5 clamp is highly dynamic,
and that there are multiple modes of peptide binding and mobility throughout the
complex. Although this interaction is of very high affinity, relatively few
persistent contacts are found between the peptide and the Ppp5-TPR domain, thus
explaining its promiscuity in binding both Hsp70 and Hsp90 in vivo. We consider
the possible implications of this dynamic structure for the mechanism of relief
of autoinhibition in Ppp5 and for the mechanisms of TPR-mediated recognition of
Hsp90 by other proteins.
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Figure 3.
Figure 3. Structural and Dynamic Features of the Hsp90
Peptide Binding Site
(A) Conserved polar two-carboxylate
clamp residues are shown in purple; additional residues
consistently involved in ligand binding are shown in pale blue.
Residues that are physically distinct between Hop and Ppp5 and
whose variation is responsible for the different binding modes
of the Hsp90 peptide between those complexes are shown in gray.
(B) Extent of side chain assignment shown on the surface of
the TPR domain (rotated 90° with respect to [A]). Unassigned
resonances are shown in red, assigned resonances are shown in
green, and the peptide is shown as a stick model. The absence of
side chain resonances from the spectra suggests that the
affected chemical groups are undergoing significant microsecond
to millisecond timescale motion.
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Figure 7.
Figure 7. Implications of the Structure for Relief of
Autoinibition of Ppp5
Structures of the Hsp90 peptide bound
TPR domains from Ppp5-TPR and Hop-TPR2A are superimposed on the
structure of the autoinhibited form of Ppp5. The probable
directions of continuation of the Hsp90 polypeptide chain are
indicated by the dashed lines. A model based on the Hop
structure suggested direct displacement of the αJ helix, which
forms part of the autoinhibitory interface. The actual structure
of the Ppp5-TPR/peptide complex suggests that such competition
does not occur, and that displacement of α7 of the domain as a
result of ligand binding instead disrupts the αJ interaction.
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The above figures are
reprinted
by permission from Cell Press:
Structure
(2006,
14,
415-426)
copyright 2006.
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