The 2.35 å crystal structure of the inactivated form of chicken src: a dynamic molecule with multiple regulatory interactions

Williams, John C.; Weijland, Albert; Gonfloni, Stefania; Thompson, A.; Courtneidge, Sara A.; Superti‐Furga, Giulio; Wierenga, Rik K.

doi:10.1006/jmbi.1997.1426

Cited by 235 publications

(190 citation statements)

References 56 publications

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“…This structure showed how phosphorylation of Tyr 394 pinned the activation loop in an active conformation very similar to that observed in cyclic AMP-dependent kinase (Knighton et al, 1991a, b), but quite different from that observed in the autoinhibited insulin receptor kinase (Figure 3, right panel) (Hubbard et al, 1994). Furthermore, it has provided an important reference point for comparisons with the conformation of the inactive kinase and in efforts to understand mechanistically the rearrangements that lead to activation (Schindler et al, 1999;Sicheri et al, 1997;Williams et al, 1997;Xu et al, 1997Xu et al, , 1999. Crystallographic analysis of numerous tyrosine and serine/threonine kinases in both active and inactive conformations has revealed a diverse set of structural deformations that lead to loss of catalytic function in inactive kinases (Huse and Kuriyan, 2002).…”

Section: Structure and Regulation Of Src Kinases Tj Boggon And Mj Eckmentioning

confidence: 59%

“…Comparison of inactive kinases shows substantial conformational variability, as distinct regulatory mechanisms involving phosphorylation, interdomain, and protein-protein interactions impinge upon these plastic elements of the catalytic core to control kinase activity in particular pathways. In Src, the SH3 and SH2 domains and phosphorylation of the activation loop and C-terminal tail comprise the key regulatory elements Williams et al, 1997;Xu et al, 1997Xu et al, , 1999Schindler et al, 1999).…”

Section: Structure and Regulation Of Src Kinases Tj Boggon And Mj Eckmentioning

confidence: 99%

“…Rather, these domains lock the kinase domain in an inactive conformation ( Figure 5). The principle distortions of the active site that render it inactive are (i) the displacement of the C helix, which removes the catalytically important Glu 310 from the active site cleft, (ii) the activation loop adopts an a-helical conformation, which precludes binding of peptide substrates and also sequesters Tyr 416, making it inaccessible for phosphorylation, and (iii) the relative orientation of the N and C lobes is constrained in an orientation that may not be optimal for catalysis Williams et al, 1997;Xu et al, 1997Xu et al, , 1999Schindler et al, 1999).…”

Section: Structure Of the Unique Domain Of Lckmentioning

confidence: 99%

“…The inactivating phosphorylation on Tyr 527 is carried out by the Src-specific kinase Csk (Nada et al, 1991) or its homolog Chk (Hamaguchi et al, 1996;Davidson et al, 1997). Phosphorylation of the C-terminal tail promotes assembly of the SH2, SH3, and kinase domains into an autoinhibited conformation maintained by intimate interactions among these domains Williams et al, 1997;Xu et al, 1997).…”

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confidence: 99%

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Structure and regulation of Src family kinases

2004

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Src family kinases are prototypical modular signaling proteins. Their conserved domain organization includes a myristoylated N-terminal segment followed by SH3, SH2, and tyrosine kinase domains, and a short C-terminal tail. Structural dissection of Src kinases has elucidated the canonical mechanisms of phosphotyrosine recognition by the SH2 domain and proline-motif recognition by the SH3 domain. Crystallographic analysis of nearly intact Src kinases in the autoinhibited state has shown that these protein interaction motifs turn inward and lock the kinase in an inactive conformation via intramolecular interactions. The autoinhibited Src kinase structures reveal a mode of domain assembly used by other tyrosine kinases outside the Src family, including Abl and likely Tec family kinases. Furthermore, they illustrate the underlying regulatory principles that have proven to be general among diverse modular signaling proteins. Although there is considerable structural information available for the autoinhibited conformation of Src kinases, how they may assemble into active signaling complexes with substrates and regulators remains largely unexplored.

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Section: Structure and Regulation Of Src Kinases Tj Boggon And Mj Eckmentioning

confidence: 59%

Section: Structure and Regulation Of Src Kinases Tj Boggon And Mj Eckmentioning

confidence: 99%

Section: Structure Of the Unique Domain Of Lckmentioning

confidence: 99%

mentioning

confidence: 99%

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Structure and regulation of Src family kinases

2004

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“…The crystal structures of the inactive ("closed") forms of c-Src [6][7][8] and Hck [9,10] reveal that intramolecular interactions involving the SH2 and SH3 domains are essential for suppression of kinase activity despite being far away from the active site. In fact, these regulatory domains are bound to the distal side of the catalytic domain, restricting its conformational flexibility to hinder productive ATP binding.…”

Section: Introductionmentioning

confidence: 99%

Effect of the SH3-SH2 domain linker sequence on the structure of Hck kinase

Meiselbach

Sticht

2010

J Mol Model

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The coordination of activity in biological systems requires the existence of different signal transduction pathways that interact with one another and must be precisely regulated. The Src-family tyrosine kinases, which are found in many signaling pathways, differ in their physiological function despite their high overall structural similarity. In this context, the differences in the SH3-SH2 domain linkers might play a role for differential regulation, but the structural consequences of linker sequence are yet poorly understood. We have therefore performed comparative molecular dynamics simulations of wildtype Hck and of a mutant Hck, in which the SH3-SH2 domain linker is replaced by the sequence from the homologous kinase Lck. The simulations reveal that linker replacement does not only affect the orientation of the SH3 domain itself, but also leads to an alternative conformation of the activation segment in the Hck kinase domain. The sequence of the SH3-SH2 domain linker thus exerts a remote effect on the active site geometry and might therefore play a role in modulating the structure of the inactive kinase or for the fine-tuning of the activation process itself.

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NMR structure of phospho-tyrosine signaling complexes

et al. 1999

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A structural basis for activation and substrate specificity of src tyrosine kinases, and regulation of protein–protein association by tyrosine phosphorylation is described. Lyn, a src‐family tyrosine kinase, recognizes and phosphorylates the immunoreceptor tyrosine‐based activation motif, ITAM, a critical component in transmembrane signal transduction in hemopoietic cells. The structure of an ITAM peptide substrate bound to an active form of Lyn tyrosine kinase was determined by high‐resolution NMR, and a model of the complex was generated using the crystallographic structure of Lck, a closely related Src‐family kinase. The results provide a rationale for the conserved ITAM residues and specificity of Lyn, and suggest that substrate plays a role in stabilizing the kinase conformation optimal for catalysis. It is our hope that the Lck‐ITAM peptide model complex will be useful in aiding structure‐based drug design efforts that target substrate binding determinants in the design. Concerning the regulation of protein–protein association, we report on a complex between erythrocyte band 3 and two glycolytic enzymes, aldolase and glyceraldehyde‐3‐phosphate dehydrogenase. The formation of this complex is negatively regulated by tyrosine phosphorylation of band 3 by p72syk tyrosine kinase. In red blood cells, this association results in a decrease in glycolysis due to competitive inhibition of the glycolytic enzymes. The structure of band 3 recognized by the glycolytic enzymes was determined by solution NMR, and found to be a loop structure with tyrosine centrally positioned and excluded from intermolecular contact. This phosphorylation sensitive interaction, or PSI, loop may be the basis of a general mechanism for negative regulation through tyrosine phosphorylation. © 1999 John Wiley & Sons, Inc. Med Res Rev, 19, No. 4, 295–305, 1999.

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The 2.35 å crystal structure of the inactivated form of chicken src: a dynamic molecule with multiple regulatory interactions

Cited by 235 publications

References 56 publications

Structure and regulation of Src family kinases

Structure and regulation of Src family kinases

Effect of the SH3-SH2 domain linker sequence on the structure of Hck kinase

NMR structure of phospho-tyrosine signaling complexes

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