8G1Q

Co-crystal structure of Compound 1 in complex with the bromodomain of human SMARCA4 and pVHL:ElonginC:ElonginB

Summary for 8G1Q

• Entry DOI: 10.2210/pdb8g1q/pdb
• Related: 8G1P
• Descriptor: Transcription activator BRG1, Elongin-B, Elongin-C, ... (8 entities in total)
• Functional Keywords: ternary complex, protacs, transcription, gene regulation
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 56767.95

Authors

Ghimire Rijal, S.,Wurz, R.P.,Vaish, A. (deposition date: 2023-02-02, release date: 2023-07-26, Last modification date: 2023-08-30)

Primary citation

Wurz, R.P.,Rui, H.,Dellamaggiore, K.,Ghimire-Rijal, S.,Choi, K.,Smither, K.,Amegadzie, A.,Chen, N.,Li, X.,Banerjee, A.,Chen, Q.,Mohl, D.,Vaish, A.
Affinity and cooperativity modulate ternary complex formation to drive targeted protein degradation.
Nat Commun, 14:4177-4177, 2023

PubMed Abstract: Targeted protein degradation via "hijacking" of the ubiquitin-proteasome system using proteolysis targeting chimeras (PROTACs) has evolved into a novel therapeutic modality. The design of PROTACs is challenging; multiple steps involved in PROTAC-induced degradation make it difficult to establish coherent structure-activity relationships. Herein, we characterize PROTAC-mediated ternary complex formation and degradation by employing von Hippel-Lindau protein (VHL) recruiting PROTACs for two different target proteins, SMARCA2 and BRD4. Ternary-complex attributes and degradation activity parameters are evaluated by varying components of the PROTAC's architecture. Ternary complex binding affinity and cooperativity correlates well with degradation potency and initial rates of degradation. Additionally, we develop a ternary-complex structure modeling workflow to calculate the total buried surface area at the interface, which is in agreement with the measured ternary complex binding affinity. Our findings establish a predictive framework to guide the design of potent degraders.

PubMed: 37443112
DOI: 10.1038/s41467-023-39904-5

Experimental method

X-RAY DIFFRACTION (3.73 Å)