Design of small molecules that compete with nucleotide binding to an engineered oncogenic KRAS allele
| Autor: | Marie-Hélène Larraufie, Yan Zhang, Lewis M. Brown, Brent R. Stockwell, Leila S. Musavi, Hemanth Akkiraju |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Neuroblastoma RAS viral oncogene homolog Gene isoform Models Molecular GTP' medicine.disease_cause Protein Engineering 01 natural sciences Biochemistry Guanosine Diphosphate Article Proto-Oncogene Proteins p21(ras) Small Molecule Libraries 03 medical and health sciences medicine Humans Nucleotide HRAS Amino Acid Sequence Binding site neoplasms chemistry.chemical_classification Binding Sites 010405 organic chemistry Chemistry Small molecule digestive system diseases 0104 chemical sciences Cell biology 030104 developmental biology Drug Design Mutation KRAS Guanosine Triphosphate Protein Binding |
| Popis: | RAS mutations are found in 30% of all human cancers, with KRAS the most frequently mutated among the three RAS isoforms (KRAS, NRAS, and HRAS). However, directly targeting oncogenic KRAS with small molecules in the nucleotide-binding site has been difficult because of the high affinity of KRAS for GDP and GTP. We designed an engineered allele of KRAS and a covalent inhibitor that competes for GTP and GDP. This ligand–receptor combination demonstrates that the high affinity of GTP and GDP for RAS proteins can be overcome with a covalent inhibitor and a suitably engineered binding site. The covalent inhibitor irreversibly modifies the protein at the engineered nucleotide-binding site and is able to compete with GDP and GTP. This provides a new tool for studying KRAS function and suggests strategies for targeting the nucleotide-binding site of oncogenic RAS proteins. |
| Databáze: | OpenAIRE |
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