7U3H

GID4 in complex with compound 7

7U3H の概要

• エントリーDOI: 10.2210/pdb7u3h/pdb
• 分子名称: Glucose-induced degradation protein 4 homolog, (5R)-N-(4-fluorophenyl)-5-methyl-4,5-dihydro-1,3-thiazol-2-amine (3 entities in total)
• 機能のキーワード: complex, inhibitor, protein degradation, peptide binding protein, peptide binding protein-inhibitor complex, peptide binding protein/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19815.05

構造登録者

Chana, C.K.,Sicheri, F. (登録日: 2022-02-27, 公開日: 2022-10-05, 最終更新日: 2023-10-18)

主引用文献

Chana, C.K.,Maisonneuve, P.,Posternak, G.,Grinberg, N.G.A.,Poirson, J.,Ona, S.M.,Ceccarelli, D.F.,Mader, P.,St-Cyr, D.J.,Pau, V.,Kurinov, I.,Tang, X.,Deng, D.,Cui, W.,Su, W.,Kuai, L.,Soll, R.,Tyers, M.,Rost, H.L.,Batey, R.A.,Taipale, M.,Gingras, A.C.,Sicheri, F.
Discovery and Structural Characterization of Small Molecule Binders of the Human CTLH E3 Ligase Subunit GID4.
J.Med.Chem., 65:12725-12746, 2022

PubMed Abstract: Targeted protein degradation (TPD) strategies exploit bivalent small molecules to bridge substrate proteins to an E3 ubiquitin ligase to induce substrate degradation. Few E3s have been explored as degradation effectors due to a dearth of E3-binding small molecules. We show that genetically induced recruitment to the GID4 subunit of the CTLH E3 complex induces protein degradation. An NMR-based fragment screen followed by structure-guided analog elaboration identified two binders of GID4, and , with values of 110 and 17 μM . A parallel DNA-encoded library (DEL) screen identified five binders of GID4, the best of which, , had a of 5.6 μM and an EC of 558 nM in cells with strong selectivity for GID4. X-ray co-structure determination revealed the basis for GID4-small molecule interactions. These results position GID4-CTLH as an E3 for TPD and provide candidate scaffolds for high-affinity moieties that bind GID4.

PubMed: 36117290
DOI: 10.1021/acs.jmedchem.2c00509

実験手法

X-RAY DIFFRACTION (1.798 Å)