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PDBsum entry 3esk
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References listed in PDB file
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Key reference
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Title
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Electrostatic interactions of hsp-Organizing protein tetratricopeptide domains with hsp70 and hsp90: computational analysis and protein engineering.
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Authors
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T.Kajander,
J.N.Sachs,
A.Goldman,
L.Regan.
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Ref.
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J Biol Chem, 2009,
284,
25364-25374.
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PubMed id
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Abstract
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The Hsp-organizing protein (HOP) binds to the C termini of the chaperones Hsp70
and Hsp90, thus bringing them together so that substrate proteins can be passed
from Hsp70 to Hsp90. Because Hsp90 is essential for the correct folding and
maturation of many oncogenic proteins, it has become a significant target for
anti-cancer drug design. HOP binds to Hsp70 and Hsp90 via two independent
tetratricopeptide (TPR) domains, TPR1 and TPR2A, respectively. We have analyzed
ligand binding using Poisson-Boltzmann continuum electrostatic calculations,
free energy perturbation, molecular dynamics simulations, and site-directed
mutagenesis to delineate the contribution of different interactions to the
affinity and specificity of the TPR-peptide interactions. We found that
continuum electrostatic calculations could be used to guide protein design by
removing unfavorable interactions to increase binding affinity, with an 80-fold
increase in affinity for TPR2A. Contributions at buried charged residues,
however, were better predicted by free energy perturbation calculations. We
suggest using a combination of the two approaches for increasing the accuracy of
results, with free energy perturbation calculations used only at selected buried
residues of the ligand binding pocket. Finally we present the crystal structure
of TPR2A in complex with its non-cognate Hsp70 ligand, which provides insight on
the origins of specificity in TPR domain-peptide recognition.
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