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PDBsum entry 5ih2
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Signaling protein
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PDB id
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5ih2
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References listed in PDB file
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Key reference
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Title
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Binding mechanism of the n-Terminal sh3 domain of crkii and proline-Rich motifs in cabl.
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Authors
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V.S.Bhatt,
D.Zeng,
I.Krieger,
J.C.Sacchettini,
J.H.Cho.
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Ref.
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Biophys J, 2016,
110,
2630-2641.
[DOI no: ]
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PubMed id
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Abstract
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The N-terminal Src homology 3 (nSH3) domain of a signaling adaptor protein,
CT-10 regulator of kinase II (CrkII), recognizes proline-rich motifs (PRMs) of
binding partners, such as cAbl kinase. The interaction between CrkII and cAbl
kinase is involved in the regulation of cell spreading, microbial pathogenesis,
and cancer metastasis. Here, we report the detailed biophysical
characterizations of the interactions between the nSH3 domain of CrkII and PRMs
in cAbl. We identified that the nSH3 domain of CrkII binds to three PRMs in cAbl
with virtually identical affinities. Structural studies, by using x-ray
crystallography and NMR spectroscopy, revealed that the binding modes of all
three nSH3:PRM complexes are highly similar to each other. Van 't Hoff analysis
revealed that nSH3:PRM interaction is associated with favorable enthalpy and
unfavorable entropy change. The combination of experimentally determined
thermodynamic parameters, structure-based calculations, and (15)N NMR relaxation
analysis highlights the energetic contribution of conformational entropy change
upon the complex formation, and water molecules structured in the binding
interface of the nSH3:PRM complex. Understanding the molecular basis of nSH3:PRM
interaction will provide, to our knowledge, new insights for the rational design
of small molecules targeting the interaction between CrkII and cAbl.
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