RAS effector-binding interface (RAS-EBI)

RAS proteins (KRAS, HRAS, and NRAS) function as binary molecular switches that cycle between an inactive GDP-bound state and an active GTP-bound state (Cox et al., 2014, Nature Reviews Drug Discovery). The active state undergoes a conformational change in two flexible regions, Switch I and Switch II, which form the RAS effector-binding interface. This interface is responsible for recruiting and activating downstream signaling effectors such as RAF kinases, phosphoinositide 3-kinases (PI3K), and Ral guanine nucleotide dissociation stimulants (RalGDS) (Stephen et al., 2014, Cancer Cell). In many human cancers, mutations in RAS lock the protein in the active state, leading to persistent signaling through these interfaces and driving uncontrolled cell proliferation and survival. Historically considered undruggable due to the smooth surface of RAS, the effector-binding interface is now a primary target for therapeutic intervention. Modern drug discovery efforts focus on small molecules and monobodies that competitively inhibit these protein-protein interactions or allosterically modulate the interface to prevent effector recruitment (Kessler et al., 2019, PNAS). Therapeutic strategies targeting this interface aim to selectively inhibit oncogenic signaling while minimizing impact on normal cellular functions. However, challenges such as feedback activation and resistance mutations remain significant hurdles in the clinical application of these inhibitors (Moore et al., 2020, Nature Reviews Clinical Oncology).

Other names

RAS-effector interfaceRAS-binding domain (RBD) interfaceSwitch I/II effector-binding siteRAS-RAF interaction interface

Inhibition of protein-protein interactions (PPIs) between RAS and its downstream effectors (e.g., RAF, PI3K) by binding to the Switch I/II regions or allosterically preventing the active conformation (Kessler et al., 2019, PNAS; Athuluri-Divakar et al., 2016, Cell).