EMD-24742
PSMD2 with bound macrocycle MC1
EMD-24742
Single-particle2.5 Å
Deposition: 25/08/2021Map released: 31/08/2022
Last modified: 11/01/2023
Sample Organism:
Homo sapiens
Sample: PSMD2 with bound macrocycle MC1
Deposition Authors: Johnson MC
,
Bashore C,
Ciferri C ,
Dueber EC
Sample: PSMD2 with bound macrocycle MC1
Deposition Authors: Johnson MC
,
Bashore C,
Ciferri C ,
Dueber EC
Targeted degradation via direct 26S proteasome recruitment.
Bashore C,
Prakash S ,
Johnson MC ,
Conrad RJ,
Kekessie IA,
Scales SJ ,
Ishisoko N,
Kleinheinz T,
Liu PS,
Popovych N,
Wecksler AT,
Zhou L,
Tam C,
Zilberleyb I,
Srinivasan R,
Blake RA,
Song A,
Staben ST,
Zhang Y,
Arnott D,
Fairbrother WJ,
Foster SA,
Wertz IE ,
Ciferri C ,
Dueber EC
(2023) Nat Chem Biol , 19 , 55 - 63
,
Johnson MC ,
Conrad RJ,
Kekessie IA,
Scales SJ ,
Ishisoko N,
Kleinheinz T,
Liu PS,
Popovych N,
Wecksler AT,
Zhou L,
Tam C,
Zilberleyb I,
Srinivasan R,
Blake RA,
Song A,
Staben ST,
Zhang Y,
Arnott D,
Fairbrother WJ,
Foster SA,
Wertz IE ,
Ciferri C ,
Dueber EC
(2023) Nat Chem Biol , 19 , 55 - 63
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.
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.