7M2K

CDC34A-Ubiquitin-2ab inhibitor complex

7M2K の概要

• エントリーDOI: 10.2210/pdb7m2k/pdb
• 分子名称: Ubiquitin-conjugating enzyme E2 R1, Ubiquitin, 4-[(3',5'-dichloro[1,1'-biphenyl]-4-yl)methyl]-N-ethyl-1-(methoxyacetyl)piperidine-4-carboxamide, ... (4 entities in total)
• 機能のキーワード: ubiquitin, ube2r1, ubiquitin conjugating enzyme, inhibitor, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 119427.07

構造登録者

Ceccarelli, D.F.,St-Cyr, D.,Tyers, M.,Sicheri, F. (登録日: 2021-03-16, 公開日: 2021-11-03, 最終更新日: 2023-10-18)

主引用文献

St-Cyr, D.,Ceccarelli, D.F.,Orlicky, S.,van der Sloot, A.M.,Tang, X.,Kelso, S.,Moore, S.,James, C.,Posternak, G.,Coulombe-Huntington, J.,Bertomeu, T.,Marinier, A.,Sicheri, F.,Tyers, M.
Identification and optimization of molecular glue compounds that inhibit a noncovalent E2 enzyme-ubiquitin complex.
Sci Adv, 7:eabi5797-eabi5797, 2021

PubMed Abstract: Pharmacological control of the ubiquitin-proteasome system (UPS) is of intense interest in drug discovery. Here, we report the development of chemical inhibitors of the ubiquitin-conjugating (E2) enzyme CDC34A (also known as UBE2R1), which donates activated ubiquitin to the cullin-RING ligase (CRL) family of ubiquitin ligase (E3) enzymes. A FRET-based interaction assay was used to screen for novel compounds that stabilize the noncovalent complex between CDC34A and ubiquitin, and thereby inhibit the CDC34A catalytic cycle. An isonipecotamide hit compound was elaborated into analogs with ~1000-fold increased potency in stabilizing the CDC34A-ubiquitin complex. These analogs specifically inhibited CDC34A-dependent ubiquitination in vitro and stabilized an E2~ubiquitin thioester reaction intermediate in cells. The x-ray crystal structure of a CDC34A-ubiquitin-inhibitor complex uncovered the basis for analog structure-activity relationships. The development of chemical stabilizers of the CDC34A-ubiquitin complex illustrates a general strategy for de novo discovery of molecular glue compounds that stabilize weak protein interactions.

PubMed: 34705497
DOI: 10.1126/sciadv.abi5797

実験手法

X-RAY DIFFRACTION (2.47 Å)