9I7Y
Crystal Structure of KRasG13C in Complex with Nucleotide-based Covalent Inhibitor 7b
This is a non-PDB format compatible entry.
Summary for 9I7Y
| Entry DOI | 10.2210/pdb9i7y/pdb |
| Descriptor | Isoform 2B of GTPase KRas, [(2~{R},3~{S},4~{R},5~{R})-5-(2-azanyl-6-oxidanylidene-1~{H}-purin-9-yl)-4-oxidanyl-2-[[oxidanyl(phosphonooxy)phosphoryl]oxymethyl]oxolan-3-yl] (3~{S})-3-(propanoylamino)piperidine-1-carboxylate, MAGNESIUM ION, ... (4 entities in total) |
| Functional Keywords | kras, gtpase, nucleotide-based inhibitor, covalent, g13c, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 3 |
| Total formula weight | 60421.98 |
| Authors | |
| Primary citation | Kirschner, T.,Rodriguez, J.,Moreira, E.G.,Niggenaber, J.,Warmuth, J.D.,Verli, H.,Muller, M.P.,Rauh, D. Targeting KRAS G13C with cyclic linker based inhibitors to explore warhead orientation. Sci Rep, 15:38213-38213, 2025 Cited by PubMed Abstract: The small GTPase KRAS is a key driver of carcinogenesis when mutated, and significant progress has been made in targeting KRAS and other oncogenic variants. Building on our previous work demonstrating the potential of nucleotide-based inhibitors with an acrylamide warhead to target KRAS, we designed and synthesized a library of nucleotide-based compounds with cyclic linkers to explore the effect of warhead orientation on reactivity toward Cys13. Using mass spectrometry, kinetic studies, and protein X-ray crystallography, we validated the binding and reactivity of these modulators. In addition, computational predictions of the conformational space of the linkers and warheads provided insights into their reactivity, which agreed well with the experimental data. These findings advance our understanding of the structure-reactivity relationship in these nucleotide-based KRAS inhibitors and will be the basis for further optimization. PubMed: 41174214DOI: 10.1038/s41598-025-22145-5 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.85 Å) |
Structure validation
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