9QQ0
KRAS-G12D(1-169) - GDP IN covalent COMPLEX WITH compound (3R,4R)-3
This is a non-PDB format compatible entry.
Summary for 9QQ0
| Entry DOI | 10.2210/pdb9qq0/pdb |
| Descriptor | Isoform 2B of GTPase KRas, MAGNESIUM ION, SULFATE ION, ... (6 entities in total) |
| Functional Keywords | k-ras g12d, gtpase, gdp bound, switch 2 pocket, covalent binding, signaling protein, small g- protein, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 20671.08 |
| Authors | |
| Primary citation | Budai, B.,Vaupel, A.,Dickson, C.J.,Beyer, K.S.,Guthy, D.A.,Ostermann, N.,McGregor, L.M.,De Kanter, R.,Weiss, A.,Linder, M.,Sager, E.,Bomio-Confaglia, C.,Proctor, R.,Leblanc, C.,Yuan, J.,Cotesta, S.,Wilcken, R.,Danilack, A.D.,Garcia, F.,Rogemoser, P.,Kazic-Legueux, M.,Zhang, Z.,Zheng, Q.,Shokat, K.M.,Brachmann, S.M.,Ehmke, V. Promise and Challenge of beta-Lactone Electrophiles to Target Aspartate 12 of Mutant KRAS G12D. J.Med.Chem., 2025 Cited by PubMed Abstract: The clinical success of covalent KRAS inhibition prompts further expansion of the concept to target non-cysteine oncogenic mutation sites as in KRAS. This endeavor was hampered by the lack of suitable electrophiles for the selective, covalent engagement of aspartate. Thanks to the recent discovery of β-lactone-bearing covalent inhibitors, new opportunities are emerging. Based on X-ray crystallographic insights and quantum chemical calculations, we herein describe the elucidation of structure-activity and -stability correlations to advance such electrophiles for drug discovery. Guided by predictions of transition state barrier heights for the attack of aspartate 12 at the β-lactone electrophile and structure-based design, we generated substituted β-lactones aiming to balance specific reactivity and chemical and metabolic stability. Our optimization strategy is driven by MS-based and cellular covalent target occupancy assays and PD marker analysis, proteome-wide profiling, and synthetic chemistry. With this work, we aim to expand the use of β-lactones as chemoselective electrophiles in medicinal chemistry. PubMed: 40635203DOI: 10.1021/acs.jmedchem.5c01214 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.546 Å) |
Structure validation
Download full validation report
