7UJD

PSMD2 Structure bound to MC1 and Fab8/14

7UJD の概要

• エントリーDOI: 10.2210/pdb7ujd/pdb
• EMDBエントリー: 24742 24743
• 分子名称: 26S proteasome non-ATPase regulatory subunit 2, Fab 14 LC CDRs, Fab 14 HC CDRs, ... (6 entities in total)
• 機能のキーワード: 26s proteasome macrocycle, protein binding, protein binding-immune system complex, protein binding/immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 168902.22

構造登録者

Johnson, M.C.,Bashore, C.,Ciferri, C.,Dueber, E.C. (登録日: 2022-03-30, 公開日: 2023-01-11)

主引用文献

Bashore, C.,Prakash, S.,Johnson, M.C.,Conrad, R.J.,Kekessie, I.A.,Scales, S.J.,Ishisoko, N.,Kleinheinz, T.,Liu, P.S.,Popovych, N.,Wecksler, A.T.,Zhou, L.,Tam, C.,Zilberleyb, I.,Srinivasan, R.,Blake, R.A.,Song, A.,Staben, S.T.,Zhang, Y.,Arnott, D.,Fairbrother, W.J.,Foster, S.A.,Wertz, I.E.,Ciferri, C.,Dueber, E.C.
Targeted degradation via direct 26S proteasome recruitment.
Nat.Chem.Biol., 19:55-63, 2023

PubMed Abstract: Engineered destruction of target proteins by recruitment to the cell's degradation machinery has emerged as a promising strategy in drug discovery. The majority of molecules that facilitate targeted degradation do so via a select number of ubiquitin ligases, restricting this therapeutic approach to tissue types that express the requisite ligase. Here, we describe a new strategy of targeted protein degradation through direct substrate recruitment to the 26S proteasome. The proteolytic complex is essential and abundantly expressed in all cells; however, proteasomal ligands remain scarce. We identify potent peptidic macrocycles that bind directly to the 26S proteasome subunit PSMD2, with a 2.5-Å-resolution cryo-electron microscopy complex structure revealing a binding site near the 26S pore. Conjugation of this macrocycle to a potent BRD4 ligand enabled generation of chimeric molecules that effectively degrade BRD4 in cells, thus demonstrating that degradation via direct proteasomal recruitment is a viable strategy for targeted protein degradation.

PubMed: 36577875
DOI: 10.1038/s41589-022-01218-w

実験手法

ELECTRON MICROSCOPY (2.5 Å)