7UIH

PSMD2 Structure

Summary for 7UIH

• Entry DOI: 10.2210/pdb7uih/pdb
• EMDB information: 24742 24743
• Descriptor: 26S proteasome non-ATPase regulatory subunit 2, Fab 14 LC CDRs, Fab 14 HC CDRs, ... (5 entities in total)
• Functional Keywords: 26s proteasome macrocycle, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 167038.14

Authors

Johnson, M.C.,Bashore, C.,Ciferri, C.,Dueber, E.C. (deposition date: 2022-03-29, release date: 2023-01-11, Last modification date: 2024-06-12)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.1 Å)