Design of Small Molecules That Compete with Nucleotide Binding to an Engineered Oncogenic KRAS Allele
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:57 |
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| Enthalten in: |
Biochemistry - 57(2018), 8 vom: 27. Feb., Seite 1380-1389 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Yan [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.05.2018 Date Revised 14.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.biochem.7b01113 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM279766211 |
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| 500 | |a Date Revised 14.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a KRAS protein, human |2 NLM | |
| 650 | 7 | |a Small Molecule Libraries |2 NLM | |
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| 700 | 1 | |a Larraufie, Marie-Hélène |e verfasserin |4 aut | |
| 700 | 1 | |a Musavi, Leila |e verfasserin |4 aut | |
| 700 | 1 | |a Akkiraju, Hemanth |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Lewis M |e verfasserin |4 aut | |
| 700 | 1 | |a Stockwell, Brent R |e verfasserin |4 aut | |
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