8GCY

Co-crystal structure of CBL-B in complex with N-Aryl isoindolin-1-one inhibitor

8GCY の概要

• エントリーDOI: 10.2210/pdb8gcy/pdb
• 分子名称: E3 ubiquitin-protein ligase CBL-B, ZINC ION, 2-{3-[(1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl}-6-{[(3S)-3-methylpiperidin-1-yl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one, ... (7 entities in total)
• 機能のキーワード: e3 ligase, cbl-b, inhibitor, sgc, ligase, ligase-ligase inhibitor complex, ligase/ligase 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: 45979.17

構造登録者

Kimani, S.,Zeng, H.,Dong, A.,Li, Y.,Santhakumar, V.,Arrowsmith, C.H.,Edwards, A.M.,Halabelian, L.,Structural Genomics Consortium (SGC) (登録日: 2023-03-03, 公開日: 2023-03-22, 最終更新日: 2024-04-03)

主引用文献

Kimani, S.W.,Perveen, S.,Szewezyk, M.,Zeng, H.,Dong, A.,Li, F.,Ghiabi, P.,Li, Y.,Chau, I.,Arrowsmith, C.H.,Barsyte-Lovejoy, D.,Santhakumar, V.,Vedadi, M.,Halabelian, L.
The co-crystal structure of Cbl-b and a small-molecule inhibitor reveals the mechanism of Cbl-b inhibition.
Commun Biol, 6:1272-1272, 2023

PubMed Abstract: Cbl-b is a RING-type E3 ubiquitin ligase that is expressed in several immune cell lineages, where it negatively regulates the activity of immune cells. Cbl-b has specifically been identified as an attractive target for cancer immunotherapy due to its role in promoting an immunosuppressive tumor environment. A Cbl-b inhibitor, Nx-1607, is currently in phase I clinical trials for advanced solid tumor malignancies. Using a suite of biophysical and cellular assays, we confirm potent binding of C7683 (an analogue of Nx-1607) to the full-length Cbl-b and its N-terminal fragment containing the TKBD-LHR-RING domains. To further elucidate its mechanism of inhibition, we determined the co-crystal structure of Cbl-b with C7683, revealing the compound's interaction with both the TKBD and LHR, but not the RING domain. Here, we provide structural insights into a novel mechanism of Cbl-b inhibition by a small-molecule inhibitor that locks the protein in an inactive conformation by acting as an intramolecular glue.

PubMed: 38104184
DOI: 10.1038/s42003-023-05655-8

実験手法

X-RAY DIFFRACTION (1.81 Å)