7ZLR

Crystal structure of SOCS2:ElonginB:ElonginC in complex with compound 13

7ZLR の概要

• エントリーDOI: 10.2210/pdb7zlr/pdb
• 分子名称: Suppressor of cytokine signaling 2, Elongin-B, Elongin-C, ... (5 entities in total)
• 機能のキーワード: e3 ligase, suppressor of cytokine signaling, ligase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 43940.15

構造登録者

Ramachandran, S.,Ciulli, A.,Makukhin, N. (登録日: 2022-04-15, 公開日: 2023-04-26, 最終更新日: 2024-05-01)

主引用文献

Ramachandran, S.,Makukhin, N.,Haubrich, K.,Nagala, M.,Forrester, B.,Lynch, D.M.,Casement, R.,Testa, A.,Bruno, E.,Gitto, R.,Ciulli, A.
Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2.
Nat Commun, 14:6345-6345, 2023

PubMed Abstract: 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 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.

PubMed: 37816714
DOI: 10.1038/s41467-023-41894-3

実験手法

X-RAY DIFFRACTION (2.01 Å)