PDBsum entry 6ccx

Membrane protein/oncoprotein

PDB id: 6ccx

Contents

Protein chains

198 a.a.

185 a.a.

Ligands

PCW ×64

17F ×16

GNP

EWS

Metals

_MG

PDB id:

6ccx

Name:

Membrane protein/oncoprotein

Title:

Nmr data-driven model of gtpase kras-gmppnp:cmpd2 complex tethered to a nanodisc

Structure:

Apolipoprotein a-i. Chain: a, c. Fragment: unp residues 68-265. Synonym: apoa-i,apolipoprotein a1. Engineered: yes. Gtpase kras. Chain: b. Synonym: k-ras 2,ki-ras,c-k-ras,c-ki-ras. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: apoa1. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: kras, kras2, rask2. Expression_system_taxid: 562

NMR struc:

10 models

Authors:

Z.Fang,C.B.Marshall,T.Nishikawa,A.D.Gossert,J.M.Jansen,W.Jahnke, M.Ikura

Key ref:

Z.Fang et al. (2018). Inhibition of K-RAS4B by a Unique Mechanism of Action: Stabilizing Membrane-Dependent Occlusion of the Effector-Binding Site. Cell Chem Biol, 25, 1327. PubMed id: 30122370 DOI: 10.1016/j.chembiol.2018.07.009

Date:

07-Feb-18 Release date: 05-Sep-18

Protein chains

P02647  (APOA1_HUMAN) -  Apolipoprotein A-I from Homo sapiens

Seq: 267 a.a.

Struc: 198 a.a.

Protein chain

P01116  (RASK_HUMAN) -  GTPase KRas from Homo sapiens

Seq: 189 a.a.

Struc: 185 a.a.*

* PDB and UniProt seqs differ at 18 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: Chains A, C: E.C.?
• Enzyme class 3: Chain B: E.C.3.6.5.2 - small monomeric GTPase.
• Reaction: GTP + H2O = GDP + phosphate + H⁺

GTP + H2O = GDP (Bound ligand (Het Group name = GNP) matches with 81.82% similarity) + phosphate + H(+)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.chembiol.2018.07.009

Cell Chem Biol 25:1327 (2018)

PubMed id: 30122370

Inhibition of K-RAS4B by a Unique Mechanism of Action: Stabilizing Membrane-Dependent Occlusion of the Effector-Binding Site.

Z.Fang, C.B.Marshall, T.Nishikawa, A.D.Gossert, J.M.Jansen, W.Jahnke, M.Ikura.

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.