6QUW
Crystal Structure of KRAS-G12D in Complex with Natural Product-Like Compound 9b
Summary for 6QUW
| Entry DOI | 10.2210/pdb6quw/pdb |
| Descriptor | GTPase KRas, PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | ppi, kras, gtpase, cancer, oncoprotein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 40081.04 |
| Authors | Fischer, G.,Kessler, D.,Muellauer, B.,Wolkerstorfer, B. (deposition date: 2019-02-28, release date: 2019-07-31, Last modification date: 2024-05-15) |
| Primary citation | Bergner, A.,Cockcroft, X.,Fischer, G.,Gollner, A.,Hela, W.,Kousek, R.,Mantoulidis, A.,Martin, L.J.,Mayer, M.,Mullauer, B.,Siszler, G.,Wolkerstorfer, B.,Kessler, D.,McConnell, D.B. KRAS Binders Hidden in Nature. Chemistry, 25:12037-12041, 2019 Cited by PubMed Abstract: Natural products have proven to be a rich source of molecular architectures for drugs. Here, an integrated approach to natural product screening is proposed, which uncovered eight new natural product scaffolds for KRAS-the most frequently mutated oncogenic driver in human cancers, which has remained thus far undrugged. The approach combines aspects of virtual screening, fragment-based screening, structure-activity relationships (SAR) by NMR, and structure-based drug discovery to overcome the limitations in traditional natural product approaches. By using our approach, a new "snugness of fit" scoring function and the first crystal-soaking system of the active form of KRAS , the protein-ligand X-ray structures of a tricyclic indolopyrrole fungal alkaloid and an indoloisoquinolinone have been successfully elucidated. The natural product KRAS hits discovered provide fruitful ground for the optimization of highly potent natural-product-based inhibitors of the active form of oncogenic RAS. This integrated approach for screening natural products also holds promise for other "undruggable" targets. PubMed: 31231840DOI: 10.1002/chem.201902810 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.242 Å) |
Structure validation
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