title: Dynamic influences on a high-affinity, high-specificity interaction involving the C-terminal SH3 domain of p67phox.
abstract: An analysis of the backbone dynamics of the C-terminal Src homology 3 (SH3) domain of p67(phox), p67(phox)SH3(C), in complex with a 32-residue high-affinity (K(d) = 24 nM) peptide, Pf, from the C-terminal region of p47(phox) is presented. This paper represents the first detailed analysis of the backbone dynamics and the ligand-induced changes therein of a high-affinity, high-specificity interaction involving an SH3 domain. The dynamic features are compared with those in the high-affinity, highly specific interaction between the SH3 domain of C-terminal Src kinase (Csk-SH3) and a proline-rich peptide from proline-enriched phosphatase (PEP). Both systems share common dynamic features especially in the canonical PxxP motif recognition surface where slow micro- to millisecond time scale dynamics persist on complex formation especially in several residues that are implicated in ligand recognition and in stabilizing the SH3 fold. These residues are highly conserved in SH3 domains. Ile505, which lies outside the PxxP recognition motif on p67(phox)SH3(C) and is key in conferring high specificity to the p67(phox)SH3(C)/Pf interaction, becomes more disordered upon complex formation. This behavior is similar to that seen in the residues that constitute the specificity surface in Csk-SH3.
authors.affiliation: The New York Structural Biology Center, New York, New York 10031, USA.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Dutta
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Shi
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Cruz-Chu
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Kami
authors.forename: Ranajeet
authors.initials: R
authors.lastname: Ghose
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D008024:Ligands; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000378:metabolism; D011392:Proline / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D018909:src Homology Domains; D019061:src-Family Kinases
chemical_list: D000596:Amino Acids; D008024:Ligands; D010446:Peptide Fragments; D010750:Phosphoproteins; C079789:neutrophil cytosol factor 67K; D011392:Proline; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D010744:Phosphoric Monoester Hydrolases