9PVF

KRAS complex with UM0152533 compound

This is a non-PDB format compatible entry.

Summary for 9PVF

• Entry DOI: 10.2210/pdb9pvf/pdb
• Descriptor: GTPase KRas, UM0152533, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: gtpase, inhibitor, macrocycle, signaling protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 12
• Total formula weight: 125585.93

Authors

Jo, C.,Lavoie, H.,Therrien, M. (deposition date: 2025-08-01, release date: 2026-04-22, Last modification date: 2026-06-03)

Primary citation

Tran, K.,Lavoie, H.,Wahhab, A.,Garrido, D.,Jo, C.H.,Poupart, M.A.,Arya, T.,Beautrait, A.,Killoran, R.,Dicaire-Leduc, C.,Bonneil, E.,Osborne, M.,Schuetz, D.A.,Shaikh, F.,Thibault, P.,Smith, M.J.,Marinier, A.,Therrien, M.
Targeting the H/KRAS alpha 4-beta 6-alpha 5 Allosteric Lobe with Macrocyclic Peptides.
Acs Med.Chem.Lett., 17:1154-1162, 2026

PubMed Abstract: Despite therapeutic advances against RAS mutations in cancer, acquired resistance frequently arises. Several secondary mutations at the binding sites effectively confer resistance to both Switch-II inhibitors and cyclophilin-A molecular glues. This underscores the need for RAS inhibitors that engage alternative binding pockets or operate through novel mechanisms. Here, we report the design of 10-mer macrocyclic peptides that mimic the FG-loop of the NS1 monobody, which targets the allosteric α4-α5-β6 surface of H/KRAS to disrupt RAS clustering and downstream signaling. These noncovalent inhibitors bind to H/KRAS with equivalent potencies, regardless of nucleotide state or the presence of oncogenic mutations (G12D, G12V, G13R, Q61K), and their binding site was confirmed by NMR and X-ray crystallography. Furthermore, covalent analogs targeting Cys118 were shown to label RAS and in complete cell lysates. Finally, we demonstrated that the key pharmacophores are connectable, providing a foundation for the development of smaller allosteric H/KRAS inhibitors.

PubMed: 42157834
DOI: 10.1021/acsmedchemlett.6c00078

Experimental method

X-RAY DIFFRACTION (2 Å)