9RK8
Crystal Structure of compound 3-mediated ternary complex of KRAS G12V C118S GDP with pVHL:ElonginC:ElonginB
This is a non-PDB format compatible entry.
Summary for 9RK8
| Entry DOI | 10.2210/pdb9rk8/pdb |
| Descriptor | Elongin-B, Elongin-C, von Hippel-Lindau disease tumor suppressor, ... (8 entities in total) |
| Functional Keywords | kras, tpd, protac, vhl, ternary complex, oncoprotein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 8 |
| Total formula weight | 124529.83 |
| Authors | |
| Primary citation | Vetma, V.,Puoti, I.,Karolak, N.K.,Chakraborti, S.,Diers, E.,Girardi, E.,Khan, S.,Kidd, G.,Kropatsch, K.G.,Mclennan, R.,O'Connor, S.,Samwer, M.,Trainor, N.,Whitworth, C.,Wijaya, A.J.,Wong, J.Y.F.,Zollman, D.,Farnaby, W.,Popow, J.,Ciulli, A.,Ettmayer, P.,McAulay, K. Identification of a Highly Cooperative PROTAC Degrader Targeting GTP-Loaded KRAS(On) Alleles. J.Am.Chem.Soc., 2025 Cited by PubMed Abstract: Kirsten rat sarcoma viral oncogene homologue (KRAS) is a frequently mutated oncogene in multiple types of cancer and is a high priority target for oncology drug development. There are many different KRAS mutations, including mutations that favor the GTP-loaded hydrolysis-incompetent "active" state of KRAS, KRAS(on), that can lead to tumorigenesis. However, small molecule interventions thus far have predominantly targeted single mutations of "inactive" GDP-loaded KRAS, KRAS(off), such as KRAS. Here, we address this gap through the development of heterobifunctional VHL-based PROTACs capable of engaging and degrading KRAS(on), thus addressing a wider range of KRAS mutations. By studying ternary complex affinity, stability, and binding modes using SPR and X-ray cocrystal structures, we identified PROTACs that exhibit high positive cooperativity in forming ternary complexes with VHL and GCP-loaded KRAS as representative of KRAS(on) variants. Degrader activity profiling in relevant cancer cells supported the discovery of ACBI4, a PROTAC which forms a highly stable and cooperative ternary complex between VHL and GTP-bound KRAS and which potently degrades KRAS, leading to antiproliferative effect in KRAS mutant-driven cancer cells. ACBI4 provides a new chemical tool for studying the impact of degrading KRAS(on) mutants, which is not possible with current pan-KRAS inhibitors or degraders. PubMed: 41166656DOI: 10.1021/jacs.5c10354 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.63 Å) |
Structure validation
Download full validation report
