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| Title | Targeted degradation via direct 26S proteasome recruitment. |
|---|---|
| Journal, issue, pages | Nat Chem Biol, Vol. 19, Issue 1, Page 55-63, Year 2023 |
| Publish date | Dec 28, 2022 |
 Authors | Charlene Bashore / Sumit Prakash / Matthew C Johnson / Ryan J Conrad / Ivy A Kekessie / Suzie J Scales / Noriko Ishisoko / Tracy Kleinheinz / Peter S Liu / Nataliya Popovych / Aaron T Wecksler / Lijuan Zhou / Christine Tam / Inna Zilberleyb / Rajini Srinivasan / Robert A Blake / Aimin Song / Steven T Staben / Yingnan Zhang / David Arnott / Wayne J Fairbrother / Scott A Foster / Ingrid E Wertz / Claudio Ciferri / Erin C Dueber /  |
| 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 ...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. |
 External links | Nat Chem Biol / PubMed:36577875 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.5 - 3.1 Å |
| Structure data | EMDB-24742: PSMD2 with bound macrocycle MC1 EMDB-24743: PSMD2 |
| Source |
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 Keywords |  PROTEIN BINDING / 26S proteasome macrocycle / PROTEIN BINDING/Immune System / PROTEIN BINDING-Immune System complex |
