Cargando…
The Ras dimer structure
Oncogenic mutated Ras is a key player in cancer, but despite intense and expensive approaches its catalytic center seems undruggable. The Ras dimer interface is a possible alternative drug target. Dimerization at the membrane affects cell growth signal transduction. In vivo studies indicate that pre...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208300/ https://www.ncbi.nlm.nih.gov/pubmed/34194708 http://dx.doi.org/10.1039/d1sc00957e |
_version_ | 1783708923308539904 |
---|---|
author | Rudack, Till Teuber, Christian Scherlo, Marvin Güldenhaupt, Jörn Schartner, Jonas Lübben, Mathias Klare, Johann Gerwert, Klaus Kötting, Carsten |
author_facet | Rudack, Till Teuber, Christian Scherlo, Marvin Güldenhaupt, Jörn Schartner, Jonas Lübben, Mathias Klare, Johann Gerwert, Klaus Kötting, Carsten |
author_sort | Rudack, Till |
collection | PubMed |
description | Oncogenic mutated Ras is a key player in cancer, but despite intense and expensive approaches its catalytic center seems undruggable. The Ras dimer interface is a possible alternative drug target. Dimerization at the membrane affects cell growth signal transduction. In vivo studies indicate that preventing dimerization of oncogenic mutated Ras inhibits uncontrolled cell growth. Conventional computational drug-screening approaches require a precise atomic dimer model as input to successfully access drug candidates. However, the proposed dimer structural models are controversial. Here, we provide a clear-cut experimentally validated N-Ras dimer structural model. We incorporated unnatural amino acids into Ras to enable the binding of labels at multiple positions via click chemistry. This labeling allowed the determination of multiple distances of the membrane-bound Ras-dimer measured by fluorescence and electron paramagnetic resonance spectroscopy. In combination with protein–protein docking and biomolecular simulations, we identified key residues for dimerization. Site-directed mutations of these residues prevent dimer formation in our experiments, proving our dimer model to be correct. The presented dimer structure enables computational drug-screening studies exploiting the Ras dimer interface as an alternative drug target. |
format | Online Article Text |
id | pubmed-8208300 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-82083002021-06-29 The Ras dimer structure Rudack, Till Teuber, Christian Scherlo, Marvin Güldenhaupt, Jörn Schartner, Jonas Lübben, Mathias Klare, Johann Gerwert, Klaus Kötting, Carsten Chem Sci Chemistry Oncogenic mutated Ras is a key player in cancer, but despite intense and expensive approaches its catalytic center seems undruggable. The Ras dimer interface is a possible alternative drug target. Dimerization at the membrane affects cell growth signal transduction. In vivo studies indicate that preventing dimerization of oncogenic mutated Ras inhibits uncontrolled cell growth. Conventional computational drug-screening approaches require a precise atomic dimer model as input to successfully access drug candidates. However, the proposed dimer structural models are controversial. Here, we provide a clear-cut experimentally validated N-Ras dimer structural model. We incorporated unnatural amino acids into Ras to enable the binding of labels at multiple positions via click chemistry. This labeling allowed the determination of multiple distances of the membrane-bound Ras-dimer measured by fluorescence and electron paramagnetic resonance spectroscopy. In combination with protein–protein docking and biomolecular simulations, we identified key residues for dimerization. Site-directed mutations of these residues prevent dimer formation in our experiments, proving our dimer model to be correct. The presented dimer structure enables computational drug-screening studies exploiting the Ras dimer interface as an alternative drug target. The Royal Society of Chemistry 2021-05-04 /pmc/articles/PMC8208300/ /pubmed/34194708 http://dx.doi.org/10.1039/d1sc00957e Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/ |
spellingShingle | Chemistry Rudack, Till Teuber, Christian Scherlo, Marvin Güldenhaupt, Jörn Schartner, Jonas Lübben, Mathias Klare, Johann Gerwert, Klaus Kötting, Carsten The Ras dimer structure |
title | The Ras dimer structure |
title_full | The Ras dimer structure |
title_fullStr | The Ras dimer structure |
title_full_unstemmed | The Ras dimer structure |
title_short | The Ras dimer structure |
title_sort | ras dimer structure |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208300/ https://www.ncbi.nlm.nih.gov/pubmed/34194708 http://dx.doi.org/10.1039/d1sc00957e |
work_keys_str_mv | AT rudacktill therasdimerstructure AT teuberchristian therasdimerstructure AT scherlomarvin therasdimerstructure AT guldenhauptjorn therasdimerstructure AT schartnerjonas therasdimerstructure AT lubbenmathias therasdimerstructure AT klarejohann therasdimerstructure AT gerwertklaus therasdimerstructure AT kottingcarsten therasdimerstructure AT rudacktill rasdimerstructure AT teuberchristian rasdimerstructure AT scherlomarvin rasdimerstructure AT guldenhauptjorn rasdimerstructure AT schartnerjonas rasdimerstructure AT lubbenmathias rasdimerstructure AT klarejohann rasdimerstructure AT gerwertklaus rasdimerstructure AT kottingcarsten rasdimerstructure |