8PD4

Crystal structure of TRIM58 PRY-SPRY domain

8PD4 の概要

• エントリーDOI: 10.2210/pdb8pd4/pdb
• 分子名称: E3 ubiquitin-protein ligase TRIM58 (2 entities in total)
• 機能のキーワード: e3 ligase, trim58, pry-spry, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 48469.13

構造登録者

Renatus, M.,Schroeder, M. (登録日: 2023-06-11, 公開日: 2024-01-31, 最終更新日: 2024-02-07)

主引用文献

Hoegenauer, K.,An, S.,Axford, J.,Benander, C.,Bergsdorf, C.,Botsch, J.,Chau, S.,Fernandez, C.,Gleim, S.,Hassiepen, U.,Hunziker, J.,Joly, E.,Keller, A.,Lopez Romero, S.,Maher, R.,Mangold, A.S.,Mickanin, C.,Mihalic, M.,Neuner, P.,Patterson, A.W.,Perruccio, F.,Roggo, S.,Scesa, J.,Schroder, M.,Shkoza, D.,Thai, B.,Vulpetti, A.,Renatus, M.,Reece-Hoyes, J.S.
Discovery of Ligands for TRIM58, a Novel Tissue-Selective E3 Ligase.
Acs Med.Chem.Lett., 14:1631-1639, 2023

PubMed Abstract: Redirecting E3 ligases to neo-substrates, leading to their proteasomal disassembly, known as targeted protein degradation (TPD), has emerged as a promising alternative to traditional, occupancy-driven pharmacology. Although the field has expanded tremendously over the past years, the choice of E3 ligases remains limited, with an almost exclusive focus on CRBN and VHL. Here, we report the discovery of novel ligands to the PRY-SPRY domain of TRIM58, a RING ligase that is specifically expressed in erythroid precursor cells. A DSF screen, followed by validation using additional biophysical methods, led to the identification of TRIM58 ligand . A basic SAR around the chemotype was established by utilizing a competitive binding assay employing a short FP peptide probe derived from an endogenous TRIM58 substrate. The X-ray co-crystal structure of TRIM58 in complex with gave insights into the binding mode and potential exit vectors for bifunctional degrader design.

PubMed: 38116426
DOI: 10.1021/acsmedchemlett.3c00259

実験手法

X-RAY DIFFRACTION (2.714 Å)