8QDN
NMR2 Structure of KRAS G12V (GMPPNP bound) in complex with7-fluoro-N,N-dimethyl-1-benzofuran-2-carboxamide
Summary for 8QDN
| Entry DOI | 10.2210/pdb8qdn/pdb |
| Related | 8PI0 8PIY 8QDK |
| NMR Information | BMRB: 34852 |
| Descriptor | RASK GTPase (Fragment), 7-fluoranyl-~{N},~{N}-dimethyl-1-benzofuran-2-carboxamide (2 entities in total) |
| Functional Keywords | complex, fragment, oncoprotein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 19504.97 |
| Authors | Buetikofer, M.,Orts, J. (deposition date: 2023-08-30, release date: 2024-10-16, Last modification date: 2025-05-07) |
| Primary citation | Butikofer, M.,Torres, F.,Kadavath, H.,Gamperli, N.,Abi Saad, M.J.,Zindel, D.,Coudevylle, N.,Riek, R.,Orts, J. NMR2-Based Drug Discovery Pipeline Presented on the Oncogenic Protein KRAS. J.Am.Chem.Soc., 147:13200-13209, 2025 Cited by PubMed Abstract: Fragment-based drug discovery has emerged as a powerful approach for developing therapeutics against challenging targets, including the GTPase KRAS. Here, we report an NMR-based screening campaign employing state-of-the-art techniques to evaluate a library of 890 fragments against the oncogenic KRAS G12V mutant bound to GMP-PNP. Further HSQC titration experiments identified hits with low millimolar affinities binding within the SI/SII switch region, which forms the binding interface for the effector proteins. To elucidate the binding modes, we applied NMR molecular replacement (MR) structure calculations, bypassing the need for a conventional protein resonance assignment. Traditionally, MR relies on isotope-filtered nuclear Overhauser effect spectroscopy experiments requiring double-labeled [C,N]-protein. We introduce a cost-efficient alternative using a relaxation-based filter that eliminates isotope labeling while preserving structural accuracy. Validation against standard isotopically labeled workflows confirmed the equivalence of the derived protein-ligand structures. This approach enabled the determination of 12 MR KRAS-fragment complex structures, providing critical insights into structure-activity relationships to guide ligand optimization. These results demonstrate the streamlined integration of MR into a fragment-based drug discovery pipeline composed of screening, binding characterization, and rapid structural elucidation with or without isotopic labeling. PubMed: 40228104DOI: 10.1021/jacs.4c16762 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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