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PDBsum entry 1bu1
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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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Rt loop flexibility enhances the specificity of src family sh3 domains for HIV-1 nef.
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Authors
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S.Arold,
R.O'Brien,
P.Franken,
M.P.Strub,
F.Hoh,
C.Dumas,
J.E.Ladbury.
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Ref.
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Biochemistry, 1998,
37,
14683-14691.
[DOI no: ]
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PubMed id
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Abstract
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Understanding the issue of specificity imposed in the interactions of SH3
domains has largely been addressed in studies investigating the interaction of
proline-rich amino acid sequences derived from potential ligands for these
domains. Although the interaction with this motif forms an essential platform in
the binding of SH3 domains, in many cases little specificity is observed and the
difference in affinity for so-called specific and nonspecific proline-rich
sequences is not great. Furthermore, the binding interface between an SH3 domain
and a protein ligand appears to encompass more interactions than are represented
by that involving the proline-rich motif. Here we investigate the issue of
specificity from the opposite point of view; namely, how does a ligand recognize
different SH3 domains? We present the crystal structure of the unbound SH3
domain from hemopoietic cell kinase (Hck) which is a member of the Src family of
tyrosine kinases. This structure reveals that, unlike the structures of other
Src kinase SH3 domains, the RT loop region is highly mobile and lacks a network
of hydrogen bonds that is elsewhere apparent. The RT loop has been shown to form
a major part of the binding interface between SH3 domains and HIV-1 Nef.
Thermodynamic data, derived from isothermal titration calorimetry, for the
binding of Hck SH3 to HIV-1 Nef show that the binding of Hck (KD = 1.5 microM)
is approximately an order of magnitude tighter than those of other Src family
kinases that were investigated (Fyn, Lck, and Src). This increase in affinity is
attributed to, among other effects, the inherent flexibility in the RT loop
which does not require breaking the network of hydrogen bonds to adopt the
conformation required for binding.
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