9glx
NRas-Q61R-GTP in complex with the peptide MPB3
Structural highlights
DiseaseRASN_HUMAN Defects in NRAS are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:607785. JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. Defects in NRAS are the cause of Noonan syndrome type 6 (NS6) [MIM:613224. A syndrome characterized by facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears. Other features can include short stature, a short neck with webbing or redundancy of skin, cardiac anomalies, deafness, motor delay and variable intellectual deficits.[1] Defects in NRAS are the cause of autoimmune lymphoproliferative syndrome type 4 (ALPS4) [MIM:614470. A disorder of apoptosis, characterized by chronic accumulation of non-malignant lymphocytes, defective lymphocyte apoptosis, and an increased risk for the development of hematologic malignancies.[2] FunctionRASN_HUMAN Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Publication Abstract from PubMedRAS 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. Identification and characterization of binders to a cryptic and functional pocket in KRAS.,Beyer KS, 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 CE, Leder L, Esser O, Muller L, Marzinzik A, Cebe R, Muller K, Galli GG, Tordella L, Cotesta S, Brachmann SM, Maira SM Nat Commun. 2025 Dec 2;16(1):10836. doi: 10.1038/s41467-025-65844-3. PMID:41330964[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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