1gng: Difference between revisions
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==Overview== | ==Overview== | ||
BACKGROUND: Glycogen synthase kinase-3 (GSK-3) sequentially phosphorylates, four serine residues on glycogen synthase (GS), in the sequence, SxxxSxxxSxxx-SxxxS(p), by recognizing and phosphorylating the first serine, in the sequence motif SxxxS(P) (where S(p) represents a phosphoserine)., FRATtide (a peptide derived from a GSK-3 binding protein) binds to GSK-3, and blocks GSK-3 from interacting with Axin. This inhibits the, Axin-dependent phosphorylation of beta-catenin by GSK-3. RESULTS:, Structures of uncomplexed Tyr216 phosphorylated GSK-3beta and of its, complex with a peptide and a sulfate ion both show the activation loop, adopting a conformation similar to that in the phosphorylated and active, forms of the related kinases CDK2 and ERK2. The sulfate ion, adjacent to, Val214 on the ... | BACKGROUND: Glycogen synthase kinase-3 (GSK-3) sequentially phosphorylates, four serine residues on glycogen synthase (GS), in the sequence, SxxxSxxxSxxx-SxxxS(p), by recognizing and phosphorylating the first serine, in the sequence motif SxxxS(P) (where S(p) represents a phosphoserine)., FRATtide (a peptide derived from a GSK-3 binding protein) binds to GSK-3, and blocks GSK-3 from interacting with Axin. This inhibits the, Axin-dependent phosphorylation of beta-catenin by GSK-3. RESULTS:, Structures of uncomplexed Tyr216 phosphorylated GSK-3beta and of its, complex with a peptide and a sulfate ion both show the activation loop, adopting a conformation similar to that in the phosphorylated and active, forms of the related kinases CDK2 and ERK2. The sulfate ion, adjacent to, Val214 on the activation loop, represents the binding site for the, phosphoserine residue on 'primed' substrates. The peptide FRATtide forms a, helix-turn-helix motif in binding to the C-terminal lobe of the kinase, domain; the FRATtide binding site is close to, but does not obstruct, the, substrate binding channel of GSK-3. FRATtide (and FRAT1) does not inhibit, the activity of GSK-3 toward GS. CONCLUSIONS: The Axin binding site on, GSK-3 presumably overlaps with that for FRATtide; its proximity to the, active site explains how Axin may act as a scaffold protein promoting, beta-catenin phosphorylation. Tyrosine 216 phosphorylation can induce an, active conformation in the activation loop. Pre-phosphorylated substrate, peptides can be modeled into the active site of the enzyme, with the P1, residue occupying a pocket partially formed by phosphotyrosine 216 and the, P4 phosphoserine occupying the 'primed' binding site. | ||
==About this Structure== | ==About this Structure== | ||
1GNG is a | 1GNG is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4 and TRS as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1GNG OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: protein kinase]] | [[Category: protein kinase]] | ||
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Revision as of 15:35, 5 November 2007
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GLYCOGEN SYNTHASE KINASE-3 BETA (GSK3) COMPLEX WITH FRATTIDE PEPTIDE
OverviewOverview
BACKGROUND: Glycogen synthase kinase-3 (GSK-3) sequentially phosphorylates, four serine residues on glycogen synthase (GS), in the sequence, SxxxSxxxSxxx-SxxxS(p), by recognizing and phosphorylating the first serine, in the sequence motif SxxxS(P) (where S(p) represents a phosphoserine)., FRATtide (a peptide derived from a GSK-3 binding protein) binds to GSK-3, and blocks GSK-3 from interacting with Axin. This inhibits the, Axin-dependent phosphorylation of beta-catenin by GSK-3. RESULTS:, Structures of uncomplexed Tyr216 phosphorylated GSK-3beta and of its, complex with a peptide and a sulfate ion both show the activation loop, adopting a conformation similar to that in the phosphorylated and active, forms of the related kinases CDK2 and ERK2. The sulfate ion, adjacent to, Val214 on the activation loop, represents the binding site for the, phosphoserine residue on 'primed' substrates. The peptide FRATtide forms a, helix-turn-helix motif in binding to the C-terminal lobe of the kinase, domain; the FRATtide binding site is close to, but does not obstruct, the, substrate binding channel of GSK-3. FRATtide (and FRAT1) does not inhibit, the activity of GSK-3 toward GS. CONCLUSIONS: The Axin binding site on, GSK-3 presumably overlaps with that for FRATtide; its proximity to the, active site explains how Axin may act as a scaffold protein promoting, beta-catenin phosphorylation. Tyrosine 216 phosphorylation can induce an, active conformation in the activation loop. Pre-phosphorylated substrate, peptides can be modeled into the active site of the enzyme, with the P1, residue occupying a pocket partially formed by phosphotyrosine 216 and the, P4 phosphoserine occupying the 'primed' binding site.
About this StructureAbout this Structure
1GNG is a Protein complex structure of sequences from Homo sapiens with SO4 and TRS as ligands. Active as Transferred entry: 2.7.11.1, with EC number 2.7.1.37 Structure known Active Site: AC1. Full crystallographic information is available from OCA.
ReferenceReference
The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation., Bax B, Carter PS, Lewis C, Guy AR, Bridges A, Tanner R, Pettman G, Mannix C, Culbert AA, Brown MJ, Smith DG, Reith AD, Structure. 2001 Dec;9(12):1143-52. PMID:11738041
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