6QUX

Crystal Structure of KRAS-G12D in Complex with Natural Product-Like Compound 15

6QUX の概要

• エントリーDOI: 10.2210/pdb6qux/pdb
• 分子名称: GTPase KRas, PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: ppi, kras, gtpase, cancer, oncoprotein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 40336.31

構造登録者

Fischer, G.,Kessler, D.,Muellauer, B.,Wolkerstorfer, B. (登録日: 2019-02-28, 公開日: 2019-07-31, 最終更新日: 2024-05-15)

主引用文献

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

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: 31231840
DOI: 10.1002/chem.201902810

実験手法

X-RAY DIFFRACTION (1.62 Å)