4GL9

Crystal structure of inhibitory protein SOCS3 in complex with JAK2 kinase domain and fragment of GP130 intracellular domain

Summary for 4GL9

• Entry DOI: 10.2210/pdb4gl9/pdb
• Descriptor: Tyrosine-protein kinase, Interleukin-6 receptor subunit beta, Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3, ... (5 entities in total)
• Functional Keywords: kinase inhibitor receptor cytokine signalling, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 12
• Total formula weight: 210768.17

Authors

Kershaw, N.J.,Murphy, J.M.,Laktyushin, A.,Nicola, N.A.,Babon, J.J. (deposition date: 2012-08-14, release date: 2013-03-06, Last modification date: 2024-10-16)

Primary citation

Kershaw, N.J.,Murphy, J.M.,Liau, N.P.,Varghese, L.N.,Laktyushin, A.,Whitlock, E.L.,Lucet, I.S.,Nicola, N.A.,Babon, J.J.
SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition.
Nat.Struct.Mol.Biol., 20:469-476, 2013

PubMed Abstract: The inhibitory protein SOCS3 plays a key part in the immune and hematopoietic systems by regulating signaling induced by specific cytokines. SOCS3 functions by inhibiting the catalytic activity of Janus kinases (JAKs) that initiate signaling within the cell. We determined the crystal structure of a ternary complex between mouse SOCS3, JAK2 (kinase domain) and a fragment of the interleukin-6 receptor β-chain. The structure shows that SOCS3 binds JAK2 and receptor simultaneously, using two opposing surfaces. While the phosphotyrosine-binding groove on the SOCS3 SH2 domain is occupied by receptor, JAK2 binds in a phosphoindependent manner to a noncanonical surface. The kinase-inhibitory region of SOCS3 occludes the substrate-binding groove on JAK2, and biochemical studies show that it blocks substrate association. These studies reveal that SOCS3 targets specific JAK-cytokine receptor pairs and explains the mechanism and specificity of SOCS action.

PubMed: 23454976
DOI: 10.1038/nsmb.2519

Experimental method

X-RAY DIFFRACTION (3.9 Å)