9GLU
Crystal structure of KRasG12D-GDP in complex with the peptide MPB1
Summary for 9GLU
| Entry DOI | 10.2210/pdb9glu/pdb |
| Descriptor | Isoform 2B of GTPase KRas, Peptide MPB1, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | gtpase, signaling protein, small g-protein, hydrolase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 42968.55 |
| Authors | |
| Primary citation | Beyer, K.S.,Klein, J.,Katz, S.,Welker, P.,Lanter, M.,Guthy, D.,Pollehn, K.,Gluck-Gade, A.,Bleu, M.,Desogus, J.,Hattenberger, M.,Borrello, D.,Abdul Rahman, W.,Zink, F.,Ostermann, N.,Jahnke, W.,Dumelin, C.E.,Leder, L.,Esser, O.,Muller, L.,Marzinzik, A.,Cebe, R.,Muller, K.,Galli, G.G.,Tordella, L.,Cotesta, S.,Brachmann, S.M.,Maira, S.M. Identification and characterization of binders to a cryptic and functional pocket in KRAS. Nat Commun, 16:10836-10836, 2025 Cited by PubMed Abstract: RAS proteins control cell proliferation and activating mutations are collectively the most frequent oncogenic event observed in cancer patients, justifying investments into multiple drug discovery efforts. While RAS-directed therapeutic agents targeting either the inactive GDP-bound or the active GTP-bound state have entered the clinic, invariably resistance is observed. Mutations at drug binding sites represent a common resistance mechanism indicating the need to discover new targetable pockets in RAS. Such efforts are hindered by the small globular size of the protein, for long considered undruggable. Here we perform macrocyclic peptides mRNA and nanobody yeast display screens and discover a targetable ligand-induced pocket in RAS. In vitro and cellular experiments with the KM12 and KM12-AM nanobodies show RAS inhibition via displacement of cRAF, by affecting their protein-protein interaction via the less studied cRAF CRD domain. Further, we provide orthogonal functional validation for the discovered binding pocket via mutagenesis experiments. Notably, the discovered RAS-targeting approach enables simultaneous targeting of both GTP-bound active and GDP-bound inactive states and leaves the SwII pocket unaltered, opening possibilities of combinatorial approaches with clinically approved SwII pocket inhibitors. PubMed: 41330964DOI: 10.1038/s41467-025-65844-3 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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