7zls

co-crystal structure of SOCS2:ElonginB:ElonginC in complex with compound 13

spinqualitylabelsall models 7zls, resolution 1.92Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7zls is a 12 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.92Å Ligands: EDO, JH9 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function SOCS2_HUMAN SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. SOCS2 appears to be a negative regulator in the growth hormone/IGF1 signaling pathway. Probable substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Publication Abstract from PubMed The Src homology 2 (SH2) domain recognizes phosphotyrosine (pY) post translational modifications in partner proteins to trigger downstream signaling. Drug discovery efforts targeting the SH2 domains have long been stymied by the poor drug-like properties of phosphate and its mimetics. Here, we use structure-based design to target the SH2 domain of the E3 ligase suppressor of cytokine signaling 2 (SOCS2). Starting from the highly ligand-efficient pY amino acid, a fragment growing approach reveals covalent modification of Cys111 in a co-crystal structure, which we leverage to rationally design a cysteine-directed electrophilic covalent inhibitor MN551. We report the prodrug MN714 containing a pivaloyloxymethyl (POM) protecting group and evidence its cell permeability and capping group unmasking using cellular target engagement and in-cell (19)F NMR spectroscopy. Covalent engagement at Cys111 competitively blocks recruitment of cellular SOCS2 protein to its native substrate. The qualified inhibitors of SOCS2 could find attractive applications as chemical probes to understand the biology of SOCS2 and its CRL5 complex, and as E3 ligase handles in proteolysis targeting chimera (PROTACs) to induce targeted protein degradation. Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2.,Ramachandran S, Makukhin N, Haubrich K, Nagala M, Forrester B, Lynch DM, Casement R, Testa A, Bruno E, Gitto R, Ciulli A Nat Commun. 2023 Oct 10;14(1):6345. doi: 10.1038/s41467-023-41894-3. PMID:37816714 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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