SI/II Pocket of Ras: An Opportunity for a Once "Undruggable" Target.

ABSTRACT: Mutations on the Ras-family of small GTPases are among the most common molecular oncogenic drivers, with the HRas isoform being primarily associated with head-and-neck and genito-urinary cancers. Although once considered "undruggable," recent efforts have identified a structurally conserved surface pocket in the Ras family, designated the SI/II pocket, situated near the binding site of the guanidine exchange factor (GEF) SOS1. The SI/II pocket may represent a potential target site for a pan-Ras drug. A crystal structure representing the native state of GDP-bound HRas^G12V was generated to characterize the topology of the SI/II pocket. This native-state structure was employed, together with the published structure of GppNHp-bound HRas^G12V in state 1 (PDB ID: 4EFM), as a

SUBMITTER: Franca TCC 

PROVIDER: S-EPMC11904710 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature