6CCH
NMR data-driven model of GTPase KRas-GMPPNP tethered to a nanodisc (E3 state)
Summary for 6CCH
| Entry DOI | 10.2210/pdb6cch/pdb |
| NMR Information | BMRB: 30401 |
| Descriptor | Apolipoprotein A-I, GTPase KRas, 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE, ... (6 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 | 131301.85 |
| 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: 2018-08-29, 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 Cited by 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: 30122370DOI: 10.1016/j.chembiol.2018.07.009 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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