8QW7
Crystal Structure of compound 4 in complex with KRAS G12V C118S GDP and pVHL:ElonginC:ElonginB
Summary for 8QW7
| Entry DOI | 10.2210/pdb8qw7/pdb |
| Descriptor | Elongin-B, Elongin-C, von Hippel-Lindau disease tumor suppressor, ... (8 entities in total) |
| Functional Keywords | ternary complex, protac, e3 ligase, oncology, oncoprotein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 8 |
| Total formula weight | 124473.72 |
| Authors | Zollman, D.,Farnaby, W.,Ciulli, A. (deposition date: 2023-10-18, release date: 2023-12-06, Last modification date: 2024-10-02) |
| Primary citation | Popow, J.,Farnaby, W.,Gollner, A.,Kofink, C.,Fischer, G.,Wurm, M.,Zollman, D.,Wijaya, A.,Mischerikow, N.,Hasenoehrl, C.,Prokofeva, P.,Arnhof, H.,Arce-Solano, S.,Bell, S.,Boeck, G.,Diers, E.,Frost, A.B.,Goodwin-Tindall, J.,Karolyi-Oezguer, J.,Khan, S.,Klawatsch, T.,Koegl, M.,Kousek, R.,Kratochvil, B.,Kropatsch, K.,Lauber, A.A.,McLennan, R.,Olt, S.,Peter, D.,Petermann, O.,Roessler, V.,Stolt-Bergner, P.,Strack, P.,Strauss, E.,Trainor, N.,Vetma, V.,Whitworth, C.,Zhong, S.,Quant, J.,Weinstabl, H.,Kuster, B.,Ettmayer, P.,Ciulli, A. Targeting cancer with small-molecule pan-KRAS degraders. Science, 385:1338-1347, 2024 Cited by PubMed Abstract: Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule that potently degrades 13 out of 17 of the most prevalent oncogenic KRAS alleles. Compared with inhibition, KRAS degradation results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines, killing cancer cells while sparing models without genetic KRAS aberrations. Pharmacological degradation of oncogenic KRAS was tolerated and led to tumor regression in vivo. Together, these findings unveil a new path toward addressing KRAS-driven cancers with small-molecule degraders. PubMed: 39298590DOI: 10.1126/science.adm8684 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.36 Å) |
Structure validation
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