9BOL
Crystal structure of the complex between VHL, ElonginB, ElonginC, and compound 5
This is a non-PDB format compatible entry.
Summary for 9BOL
| Entry DOI | 10.2210/pdb9bol/pdb |
| Related | 9BJU |
| Descriptor | Elongin-B, Elongin-C, von Hippel-Lindau disease tumor suppressor, ... (8 entities in total) |
| Functional Keywords | vhl, degradation, degrader, transcription |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 6 |
| Total formula weight | 87795.04 |
| Authors | Murray, J.M.,Wu, H.,Fuhrmann, J.,Fairbrother, W.J.,DiPasquale, A. (deposition date: 2024-05-03, release date: 2024-05-29, Last modification date: 2024-10-16) |
| Primary citation | Wu, H.,Murray, J.,Ishisoko, N.,Frommlet, A.,Deshmukh, G.,DiPasquale, A.,Mulvihill, M.M.,Zhang, D.,Quinn, J.G.,Blake, R.A.,Fairbrother, W.J.,Fuhrmann, J. Potency-Enhanced Peptidomimetic VHL Ligands with Improved Oral Bioavailability. J.Med.Chem., 67:8585-8608, 2024 Cited by PubMed Abstract: The von Hippel-Lindau (VHL) protein plays a pivotal role in regulating the hypoxic stress response and has been extensively studied and utilized in the targeted protein degradation field, particularly in the context of bivalent degraders. In this study, we present a comprehensive peptidomimetic structure-activity relationship (SAR) approach, combined with cellular NanoBRET target engagement assays to enhance the existing VHL ligands. Through systematic modifications of the molecule, we identified the 1,2,3-triazole group as an optimal substitute of the left-hand side amide bond that yields 10-fold higher binding activity. Moreover, incorporating conformationally constrained alterations on the methylthiazole benzylamine moiety led to the development of highly potent VHL ligands with picomolar binding affinity and significantly improved oral bioavailability. We anticipate that our optimized VHL ligand, , will serve as a valuable tool compound for investigating the VHL pathway and advancing the field of targeted protein degradation. PubMed: 38809766DOI: 10.1021/acs.jmedchem.3c02203 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.99 Å) |
Structure validation
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