6CCX

NMR data-driven model of GTPase KRas-GMPPNP:Cmpd2 complex tethered to a nanodisc

Summary for 6CCX

• Entry DOI: 10.2210/pdb6ccx/pdb
• NMR Information: BMRB: 30403
• Descriptor: Apolipoprotein A-I, GTPase KRas, 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE, ... (7 entities in total)
• Functional Keywords: protein-bilayer-compound complex, membrane protein-oncoprotein complex, membrane protein/oncoprotein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 131749.63

Authors

Fang, Z.,Marshall, C.B.,Nishikawa, T.,Gossert, A.D.,Jansen, J.M.,Jahnke, W.,Ikura, M. (deposition date: 2018-02-07, release date: 2018-09-05, Last modification date: 2024-05-15)

Primary citation

Fang, Z.,Marshall, C.B.,Nishikawa, T.,Gossert, A.D.,Jansen, J.M.,Jahnke, W.,Ikura, M.
Inhibition of K-RAS4B by a Unique Mechanism of Action: Stabilizing Membrane-Dependent Occlusion of the Effector-Binding Site.
Cell Chem Biol, 25:1327-1336.e4, 2018

PubMed Abstract: KRAS is frequently mutated in several of the most lethal types of cancer; however, the KRAS protein has proven a challenging drug target. K-RAS4B must be localized to the plasma membrane by prenylation to activate oncogenic signaling, thus we endeavored to target the protein-membrane interface with small-molecule compounds. While all reported lead compounds have low affinity for KRAS in solution, the potency of Cmpd2 was strongly enhanced when prenylated K-RAS4B is associated with a lipid bilayer. We have elucidated a unique mechanism of action of Cmpd2, which simultaneously engages a shallow pocket on KRAS and associates with the lipid bilayer, thereby stabilizing KRAS in an orientation in which the membrane occludes its effector-binding site, reducing RAF binding and impairing activation of RAF. Furthermore, enrichment of Cmpd2 on the bilayer enhances potency by promoting interaction with KRAS. This insight reveals a novel approach to developing inhibitors of membrane-associated proteins.

PubMed: 30122370
DOI: 10.1016/j.chembiol.2018.07.009

Experimental method

SOLUTION NMR