9BAJ
Crystal structure of GDP-bound human K-RAS in a covalent complex with aryl sulfonyl fluoride compounds.
This is a non-PDB format compatible entry.
Summary for 9BAJ
| Entry DOI | 10.2210/pdb9baj/pdb |
| Descriptor | Isoform 2B of GTPase KRas, MAGNESIUM ION, 3-(dioxo-lambda~6~-sulfanyl)-N-phenylbenzene-1-sulfonamide, ... (7 entities in total) |
| Functional Keywords | kras, cancer, gtpase, covalent inhibitor, sulfonyl fluoride, hydrolase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 80114.20 |
| Authors | Landgraf, A.D.,Brenner, R.J.,Ghozayel, M.K.,Bum-Erdene, K.,Gonzalez-Gutierrez, G.,Meroueh, S. (deposition date: 2024-04-04, release date: 2025-04-09, Last modification date: 2025-07-02) |
| Primary citation | Landgraf, A.D.,Brenner, R.,Ghozayel, M.K.,Bum-Erdene, K.,Gonzalez-Gutierrez, G.,Meroueh, S.O. Small-Molecule KRAS Inhibitors by Tyrosine Covalent Bond Formation. Chemmedchem, 20:e202400624-e202400624, 2025 Cited by PubMed Abstract: The development of the KRAS G12C inhibitor sotorasib is a major advance toward drugging KRAS. However, the G12C mutation is only found in about 10% of KRAS-driven tumors. KRAS possesses several tyrosine amino acids that could provide alternative sites for covalent drug development. Here, a library of aryl sulfonyl fluorides identified 1 (SOF-436) as an inhibitor of KRAS nucleotide exchange by guanine exchange factor SOS and KRAS binding to effector protein rapidly accelerated fibrosarcoma kinase (RAF). Tyr-64 is the major reaction site of 1 (SOF-436), although minor reaction at Tyr-71 is also observed. The fragment binds to the Switch II pocket of KRAS based on whole protein mass spectrometry, nucleotide exchange, effector protein binding, and nuclear magnetic resonance studies. Cocrystal structures of smaller fragments covalently bound to KRAS at Tyr-71 provide a strategy for the development of Switch I/II KRAS covalent inhibitors. A bioluminescent resonance energy transfer (NanoBRET) assay reveals that the compounds inhibit KRAS binding to RAF in mammalian cells. Although not yet suitable as chemical probes, these fragments provide starting points to develop small molecules to investigate tyrosine as a nucleophile for covalent inhibition of KRAS in tumors. PubMed: 40099978DOI: 10.1002/cmdc.202400624 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.49 Å) |
Structure validation
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