Methionine 274 Is Not the Determining Factor for Selective Inhibition of Histone Deacetylase 8 (HDAC8) by L-Shaped Inhibitors
HDAC8 is an important target in several indication areas including childhood neuroblastoma. Several isozyme selective inhibitors of HDAC8 with L-shaped structures have been developed. A theoretical study has suggested that methionine 274 (M274) would act as a “switch” that controls a transient bindi...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-10-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/19/11775 |
| _version_ | 1797478831509995520 |
|---|---|
| author | Niklas Jänsch Kim Leoni Lang Franz-Josef Meyer-Almes |
| author_facet | Niklas Jänsch Kim Leoni Lang Franz-Josef Meyer-Almes |
| author_sort | Niklas Jänsch |
| collection | DOAJ |
| description | HDAC8 is an important target in several indication areas including childhood neuroblastoma. Several isozyme selective inhibitors of HDAC8 with L-shaped structures have been developed. A theoretical study has suggested that methionine 274 (M274) would act as a “switch” that controls a transient binding pocket, which is induced upon binding of L-shaped inhibitors. This hypothesis was experimentally examined in this study. The thermostability and functionality of HDAC8 wildtype and mutant variants with exchanged M274 were analyzed using biophysical methods. Furthermore, the binding kinetics of L-shaped and linear reference inhibitors of these HDAC8 variants were determined in order to elucidate the mode of interaction. Exchange of M274 has considerable impact on enzyme activity, but is not the decisive factor for selective recognition of HDAC8 by L-shaped inhibitors. |
| first_indexed | 2024-03-09T21:38:10Z |
| format | Article |
| id | doaj.art-5975417b60444f529c6b16916b75ae2d |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:38:10Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5975417b60444f529c6b16916b75ae2d2023-11-23T20:39:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123191177510.3390/ijms231911775Methionine 274 Is Not the Determining Factor for Selective Inhibition of Histone Deacetylase 8 (HDAC8) by L-Shaped InhibitorsNiklas Jänsch0Kim Leoni Lang1Franz-Josef Meyer-Almes2Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, 64295 Darmstadt, GermanyDepartment of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, 64295 Darmstadt, GermanyDepartment of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, 64295 Darmstadt, GermanyHDAC8 is an important target in several indication areas including childhood neuroblastoma. Several isozyme selective inhibitors of HDAC8 with L-shaped structures have been developed. A theoretical study has suggested that methionine 274 (M274) would act as a “switch” that controls a transient binding pocket, which is induced upon binding of L-shaped inhibitors. This hypothesis was experimentally examined in this study. The thermostability and functionality of HDAC8 wildtype and mutant variants with exchanged M274 were analyzed using biophysical methods. Furthermore, the binding kinetics of L-shaped and linear reference inhibitors of these HDAC8 variants were determined in order to elucidate the mode of interaction. Exchange of M274 has considerable impact on enzyme activity, but is not the decisive factor for selective recognition of HDAC8 by L-shaped inhibitors.https://www.mdpi.com/1422-0067/23/19/11775HDAC inhibitorsbinding selectivitythermo stabilityHDAC8 muteins |
| spellingShingle | Niklas Jänsch Kim Leoni Lang Franz-Josef Meyer-Almes Methionine 274 Is Not the Determining Factor for Selective Inhibition of Histone Deacetylase 8 (HDAC8) by L-Shaped Inhibitors International Journal of Molecular Sciences HDAC inhibitors binding selectivity thermo stability HDAC8 muteins |
| title | Methionine 274 Is Not the Determining Factor for Selective Inhibition of Histone Deacetylase 8 (HDAC8) by L-Shaped Inhibitors |
| title_full | Methionine 274 Is Not the Determining Factor for Selective Inhibition of Histone Deacetylase 8 (HDAC8) by L-Shaped Inhibitors |
| title_fullStr | Methionine 274 Is Not the Determining Factor for Selective Inhibition of Histone Deacetylase 8 (HDAC8) by L-Shaped Inhibitors |
| title_full_unstemmed | Methionine 274 Is Not the Determining Factor for Selective Inhibition of Histone Deacetylase 8 (HDAC8) by L-Shaped Inhibitors |
| title_short | Methionine 274 Is Not the Determining Factor for Selective Inhibition of Histone Deacetylase 8 (HDAC8) by L-Shaped Inhibitors |
| title_sort | methionine 274 is not the determining factor for selective inhibition of histone deacetylase 8 hdac8 by l shaped inhibitors |
| topic | HDAC inhibitors binding selectivity thermo stability HDAC8 muteins |
| url | https://www.mdpi.com/1422-0067/23/19/11775 |
| work_keys_str_mv | AT niklasjansch methionine274isnotthedeterminingfactorforselectiveinhibitionofhistonedeacetylase8hdac8bylshapedinhibitors AT kimleonilang methionine274isnotthedeterminingfactorforselectiveinhibitionofhistonedeacetylase8hdac8bylshapedinhibitors AT franzjosefmeyeralmes methionine274isnotthedeterminingfactorforselectiveinhibitionofhistonedeacetylase8hdac8bylshapedinhibitors |