5IH2

Structure, thermodynamics, and the role of conformational dynamics in the interactions between the N-terminal SH3 domain of CrkII and proline-rich motifs in cAbl

Summary for 5IH2

• Entry DOI: 10.2210/pdb5ih2/pdb
• Descriptor: Adapter molecule crk, Proline rich Peptide, DI(HYDROXYETHYL)ETHER, ... (6 entities in total)
• Functional Keywords: sh3 domain polyproline ii motif, signaling protein
• Biological source: Mus musculus (Mouse); More
• Cellular location: Cytoplasm : Q64010
• Total number of polymer chains: 4
• Total formula weight: 17037.12

Authors

Bhatt, V.S.,Zeng, D.,Krieger, I.,Sacchettini, J.C.,Cho, J.-H. (deposition date: 2016-02-28, release date: 2016-06-29, Last modification date: 2024-10-30)

Primary citation

Bhatt, V.S.,Zeng, D.,Krieger, I.,Sacchettini, J.C.,Cho, J.H.
Binding Mechanism of the N-Terminal SH3 Domain of CrkII and Proline-Rich Motifs in cAbl.
Biophys.J., 110:2630-2641, 2016

PubMed Abstract: 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.

PubMed: 27332121
DOI: 10.1016/j.bpj.2016.05.008

Experimental method

X-RAY DIFFRACTION (1.8 Å)