KRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe.
Allosteric Site
/ drug effects
Ankyrin Repeat
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Cell Membrane
/ drug effects
Drug Design
Drug Screening Assays, Antitumor
HEK293 Cells
Histidine
/ metabolism
Humans
Isoenzymes
/ antagonists & inhibitors
Neoplasms
/ drug therapy
Peptide Library
Protein Binding
/ drug effects
Protein Multimerization
/ drug effects
Proto-Oncogene Proteins p21(ras)
/ antagonists & inhibitors
Signal Transduction
/ drug effects
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 06 2019
13 06 2019
Historique:
received:
16
10
2018
accepted:
09
05
2019
entrez:
15
6
2019
pubmed:
15
6
2019
medline:
10
7
2019
Statut:
epublish
Résumé
Inhibiting the RAS oncogenic protein has largely been through targeting the switch regions that interact with signalling effector proteins. Here, we report designed ankyrin repeat proteins (DARPins) macromolecules that specifically inhibit the KRAS isoform by binding to an allosteric site encompassing the region around KRAS-specific residue histidine 95 at the helix α3/loop 7/helix α4 interface. We show that these DARPins specifically inhibit KRAS/effector interactions and the dependent downstream signalling pathways in cancer cells. Binding by the DARPins at that region influences KRAS/effector interactions in different ways, including KRAS nucleotide exchange and inhibiting KRAS dimerization at the plasma membrane. These results highlight the importance of targeting the α3/loop 7/α4 interface, a previously untargeted site in RAS, for specifically inhibiting KRAS function.
Identifiants
pubmed: 31197133
doi: 10.1038/s41467-019-10419-2
pii: 10.1038/s41467-019-10419-2
pmc: PMC6565726
doi:
Substances chimiques
Antineoplastic Agents
0
Isoenzymes
0
KRAS protein, human
0
Peptide Library
0
Histidine
4QD397987E
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2607Subventions
Organisme : Medical Research Council
ID : MR/J000612/1
Pays : United Kingdom
Organisme : RCUK | Medical Research Council (MRC)
ID : MR/J000612/1
Pays : International
Organisme : Wellcome Trust (Wellcome)
ID : 099246/Z/12/Z
Pays : International
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