8g1p
Co-crystal structure of Compound 11 in complex with the bromodomain of human SMARCA2 and pVHL:ElonginC:ElonginB
Structural highlights
FunctionELOB_HUMAN SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex).[1] [2] The elongin BC complex seems to be involved as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes.[3] [4] Publication Abstract from PubMedTargeted 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. Affinity and cooperativity modulate ternary complex formation to drive targeted protein degradation.,Wurz RP, 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 Nat Commun. 2023 Jul 13;14(1):4177. doi: 10.1038/s41467-023-39904-5. PMID:37443112[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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