9BD2

MAGE-A3 MHD crystal soaked with KL861

これはPDB形式変換不可エントリーです。

9BD2 の概要

• エントリーDOI: 10.2210/pdb9bd2/pdb
• 分子名称: Melanoma-associated antigen 3, (furan-2-yl)[4-({(5P)-5-(1H-indazol-4-yl)-2-[3-(morpholin-4-yl)propoxy]phenyl}methyl)piperazin-1-yl]methanone (3 entities in total)
• 機能のキーワード: mage-a3, melanoma-associated antigen 3, mage, mage-a3 mhd, kl861, oncoprotein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 71555.96

構造登録者

Butrin, A.,Krone, M.W.,Li, K.,Bond, M.J.,Linhares, B.M.,Crews, C. (登録日: 2024-04-10, 公開日: 2024-09-18, 最終更新日: 2024-09-25)

主引用文献

Li, K.,Krone, M.W.,Butrin, A.,Bond, M.J.,Linhares, B.M.,Crews, C.M.
Development of Ligands and Degraders Targeting MAGE-A3.
J.Am.Chem.Soc., 146:24884-24891, 2024

PubMed Abstract: Type I melanoma antigen (MAGE) family members are detected in numerous tumor types, and expression is correlated with poor prognosis, high tumor grade, and increased metastasis. Type I MAGE proteins are typically restricted to reproductive tissues, but expression can recur during tumorigenesis. Several biochemical functions have been elucidated for them, and notably, MAGEs regulate proteostasis by serving as substrate recognition modules for E3 ligase complexes. The repertoire of E3 ligase complexes that can be hijacked for targeted protein degradation continues to expand, and MAGE-E3 complexes are an especially attractive platform given their cancer-selective expression. Additionally, type I MAGE-derived peptides are presented on cancer cell surfaces, so targeted MAGE degradation may increase antigen presentation and improve immunotherapy outcomes. Motivated by these applications, we developed novel, small-molecule ligands for MAGE-A3, a type I MAGE that is widely expressed in tumors and associates with TRIM28, a RING E3 ligase. Chemical matter was identified through DNA-encoded library (DEL) screening, and hit compounds were validated for binding to MAGE-A3. We obtained a cocrystal structure with a DEL analog and hypothesize that the small molecule binds at a dimer interface. We utilized this ligand to develop PROTAC molecules that induce MAGE-A3 degradation through VHL recruitment and inhibit the proliferation of MAGE-A3 positive cell lines. These ligands and degraders may serve as valuable probes for investigating MAGE-A3 biology and as foundations for the ongoing development of tumor-specific PROTACs.

PubMed: 39190582
DOI: 10.1021/jacs.4c05393

実験手法

X-RAY DIFFRACTION (2.24 Å)