7ujd

PSMD2 Structure bound to MC1 and Fab8/14PSMD2 Structure bound to MC1 and Fab8/14

Structural highlights 7ujd is a 6 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PSMD2_HUMAN Acts as a regulatory subunit of the 26 proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins. Binds to the intracellular domain of tumor necrosis factor type 1 receptor. The binding domain of TRAP1 and TRAP2 resides outside the death domain of TNFR1. Publication Abstract from PubMed 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-A-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. 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 Nat Chem Biol. 2023 Jan;19(1):55-63. doi: 10.1038/s41589-022-01218-w. Epub 2022 , Dec 28. PMID:36577875 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 7ujd, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image