Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase.
Protein farnesyltransferase (FTase) catalyzes an essential posttranslational lipid modification of more than 60 proteins involved in intracellular signal transduction networks. FTase inhibitors have emerged as a significant target for development of anticancer therapeutics and, more recently, for th...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2009
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| _version_ | 1797060629490565120 |
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| author | Hast, M Fletcher, S Cummings, C Pusateri, E Blaskovich, M Rivas, K Gelb, M Van Voorhis, W Sebti, S Hamilton, A Beese, L |
| author_facet | Hast, M Fletcher, S Cummings, C Pusateri, E Blaskovich, M Rivas, K Gelb, M Van Voorhis, W Sebti, S Hamilton, A Beese, L |
| author_sort | Hast, M |
| collection | OXFORD |
| description | Protein farnesyltransferase (FTase) catalyzes an essential posttranslational lipid modification of more than 60 proteins involved in intracellular signal transduction networks. FTase inhibitors have emerged as a significant target for development of anticancer therapeutics and, more recently, for the treatment of parasitic diseases caused by protozoan pathogens, including malaria (Plasmodium falciparum). We present the X-ray crystallographic structures of complexes of mammalian FTase with five inhibitors based on an ethylenediamine scaffold, two of which exhibit over 1000-fold selective inhibition of P. falciparum FTase. These structures reveal the dominant determinants in both the inhibitor and enzyme that control binding and selectivity. Comparison to a homology model constructed for the P. falciparum FTase suggests opportunities for further improving selectivity of a new generation of antimalarial inhibitors. |
| first_indexed | 2024-03-06T20:19:48Z |
| format | Journal article |
| id | oxford-uuid:2d668fdf-f79c-4fef-93d6-21a87c4f7b9b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:19:48Z |
| publishDate | 2009 |
| record_format | dspace |
| spelling | oxford-uuid:2d668fdf-f79c-4fef-93d6-21a87c4f7b9b2022-03-26T12:42:42ZStructural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2d668fdf-f79c-4fef-93d6-21a87c4f7b9bEnglishSymplectic Elements at Oxford2009Hast, MFletcher, SCummings, CPusateri, EBlaskovich, MRivas, KGelb, MVan Voorhis, WSebti, SHamilton, ABeese, LProtein farnesyltransferase (FTase) catalyzes an essential posttranslational lipid modification of more than 60 proteins involved in intracellular signal transduction networks. FTase inhibitors have emerged as a significant target for development of anticancer therapeutics and, more recently, for the treatment of parasitic diseases caused by protozoan pathogens, including malaria (Plasmodium falciparum). We present the X-ray crystallographic structures of complexes of mammalian FTase with five inhibitors based on an ethylenediamine scaffold, two of which exhibit over 1000-fold selective inhibition of P. falciparum FTase. These structures reveal the dominant determinants in both the inhibitor and enzyme that control binding and selectivity. Comparison to a homology model constructed for the P. falciparum FTase suggests opportunities for further improving selectivity of a new generation of antimalarial inhibitors. |
| spellingShingle | Hast, M Fletcher, S Cummings, C Pusateri, E Blaskovich, M Rivas, K Gelb, M Van Voorhis, W Sebti, S Hamilton, A Beese, L Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase. |
| title | Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase. |
| title_full | Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase. |
| title_fullStr | Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase. |
| title_full_unstemmed | Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase. |
| title_short | Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase. |
| title_sort | structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase |
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