4NM3

Crystal structure of GSK-3/Axin complex bound to phosphorylated N-terminal auto-inhibitory pS9 peptide

Summary for 4NM3

• Entry DOI: 10.2210/pdb4nm3/pdb
• Related: 4NM0 4NM5 4NM7 4NU1
• Descriptor: Glycogen synthase kinase-3 beta, Axin-1, GLYCEROL, ... (8 entities in total)
• Functional Keywords: wnt, lrp6, auto-inhibited, gsk-3, axin, kinase, primed substrate, phosphorylated n-terminal auto-inhibitory ps9 peptide, transferase-peptide complex, transferase/peptide
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P49841 O15169
• Total number of polymer chains: 2
• Total formula weight: 48032.64

Authors

Chu, M.L.-H.,Stamos, J.L.,Enos, M.D.,Shah, N.,Weis, W.I. (deposition date: 2013-11-14, release date: 2014-03-26, Last modification date: 2024-11-20)

Primary citation

Stamos, J.L.,Chu, M.L.,Enos, M.D.,Shah, N.,Weis, W.I.
Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6.
Elife, 3:e01998-e01998, 2014

PubMed Abstract: Glycogen synthase kinase-3 (GSK-3) is a key regulator of many cellular signaling pathways. Unlike most kinases, GSK-3 is controlled by inhibition rather than by specific activation. In the insulin and several other signaling pathways, phosphorylation of a serine present in a conserved sequence near the amino terminus of GSK-3 generates an auto-inhibitory peptide. In contrast, Wnt/β-catenin signal transduction requires phosphorylation of Ser/Pro rich sequences present in the Wnt co-receptors LRP5/6, and these motifs inhibit GSK-3 activity. We present crystal structures of GSK-3 bound to its phosphorylated N-terminus and to two of the phosphorylated LRP6 motifs. A conserved loop unique to GSK-3 undergoes a dramatic conformational change that clamps the bound pseudo-substrate peptides, and reveals the mechanism of primed substrate recognition. The structures rationalize target sequence preferences and suggest avenues for the design of inhibitors selective for a subset of pathways regulated by GSK-3. DOI: http://dx.doi.org/10.7554/eLife.01998.001.

PubMed: 24642411

Experimental method

X-RAY DIFFRACTION (2.1 Å)