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PDBsum entry 6i4x
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Signaling protein
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PDB id
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6i4x
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Contents |
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103 a.a.
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86 a.a.
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158 a.a.
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References listed in PDB file
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Key reference
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Title
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Structural insights into substrate recognition by the socs2 e3 ubiquitin ligase.
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Authors
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W.W.Kung,
S.Ramachandran,
N.Makukhin,
E.Bruno,
A.Ciulli.
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Ref.
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Nat Commun, 2019,
10,
2534.
[DOI no: ]
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PubMed id
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Abstract
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The suppressor of cytokine signaling 2 (SOCS2) acts as substrate recognition
subunit of a Cullin5 E3 ubiquitin ligase complex. SOCS2 binds to
phosphotyrosine-modified epitopes as degrons for ubiquitination and proteasomal
degradation, yet the molecular basis of substrate recognition has remained
elusive. Here, we report co-crystal structures of SOCS2-ElonginB-ElonginC in
complex with phosphorylated peptides from substrates growth hormone receptor
(GHR-pY595) and erythropoietin receptor (EpoR-pY426) at 1.98 Å and 2.69 Å,
respectively. Both peptides bind in an extended conformation recapitulating the
canonical SH2 domain-pY pose, but capture different conformations of the EF loop
via specific hydrophobic interactions. The flexible BG loop is fully defined in
the electron density, and does not contact the substrate degron directly.
Cancer-associated SNPs located around the pY pocket weaken substrate-binding
affinity in biophysical assays. Our findings reveal insights into substrate
recognition and specificity by SOCS2, and provide a blueprint for small molecule
ligand design.
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