Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange
<p>Ras mutations are the oncogenic drivers of many human cancers and yet there are still no approved Ras-targeted cancer therapies. Inhibition of Ras nucleotide exchange is a promising new approach but better understanding of this mechanism of action is needed. Here we describe an antibody mi...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Nature Publishing Group
2017
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| _version_ | 1797072620587319296 |
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| author | Guillard, S Kolasinska-Zwierz, P Debreczeni, J Breed, J Zhang, J Bery, N Marwood, R Tart, J Overman, R Stocki, P Mistry, B Phillips, C Rabbitts, T Jackson, R Minter, R |
| author_facet | Guillard, S Kolasinska-Zwierz, P Debreczeni, J Breed, J Zhang, J Bery, N Marwood, R Tart, J Overman, R Stocki, P Mistry, B Phillips, C Rabbitts, T Jackson, R Minter, R |
| author_sort | Guillard, S |
| collection | OXFORD |
| description | <p>Ras mutations are the oncogenic drivers of many human cancers and yet there are still no approved Ras-targeted cancer therapies. Inhibition of Ras nucleotide exchange is a promising new approach but better understanding of this mechanism of action is needed. Here we describe an antibody mimetic, DARPin K27, which inhibits nucleotide exchange of Ras. K27 binds preferentially to the inactive Ras GDP form with a <i>K</i><sub>d</sub> of 4 nM and structural studies support its selectivity for inactive Ras. Intracellular expression of K27 significantly reduces the amount of active Ras, inhibits downstream signalling, in particular the levels of phosphorylated ERK, and slows the growth in soft agar of HCT116 cells. K27 is a potent, non-covalent inhibitor of nucleotide exchange, showing consistent effects across different isoforms of Ras, including wild-type and oncogenic mutant forms.</p> |
| first_indexed | 2024-03-06T23:10:23Z |
| format | Journal article |
| id | oxford-uuid:6542179d-9e74-475b-af49-d00004fa38cf |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:10:23Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:6542179d-9e74-475b-af49-d00004fa38cf2022-03-26T18:24:25ZStructural and functional characterization of a DARPin which inhibits Ras nucleotide exchangeJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6542179d-9e74-475b-af49-d00004fa38cfEnglishSymplectic Elements at OxfordNature Publishing Group2017Guillard, SKolasinska-Zwierz, PDebreczeni, JBreed, JZhang, JBery, NMarwood, RTart, JOverman, RStocki, PMistry, BPhillips, CRabbitts, TJackson, RMinter, R <p>Ras mutations are the oncogenic drivers of many human cancers and yet there are still no approved Ras-targeted cancer therapies. Inhibition of Ras nucleotide exchange is a promising new approach but better understanding of this mechanism of action is needed. Here we describe an antibody mimetic, DARPin K27, which inhibits nucleotide exchange of Ras. K27 binds preferentially to the inactive Ras GDP form with a <i>K</i><sub>d</sub> of 4 nM and structural studies support its selectivity for inactive Ras. Intracellular expression of K27 significantly reduces the amount of active Ras, inhibits downstream signalling, in particular the levels of phosphorylated ERK, and slows the growth in soft agar of HCT116 cells. K27 is a potent, non-covalent inhibitor of nucleotide exchange, showing consistent effects across different isoforms of Ras, including wild-type and oncogenic mutant forms.</p> |
| spellingShingle | Guillard, S Kolasinska-Zwierz, P Debreczeni, J Breed, J Zhang, J Bery, N Marwood, R Tart, J Overman, R Stocki, P Mistry, B Phillips, C Rabbitts, T Jackson, R Minter, R Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange |
| title | Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange |
| title_full | Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange |
| title_fullStr | Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange |
| title_full_unstemmed | Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange |
| title_short | Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange |
| title_sort | structural and functional characterization of a darpin which inhibits ras nucleotide exchange |
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