Structural Elucidation of the DFG-Asp in and DFG-Asp out States of TAM Kinases and Insight into the Selectivity of Their Inhibitors
Structural elucidation of the active (DFG-Asp in) and inactive (DFG-Asp out) states of the TAM family of receptor tyrosine kinases is required for future development of TAM inhibitors as drugs. Herein we report a computational study on each of the three TAM members Tyro-3, Axl and Mer. DFG-Asp in an...
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MDPI AG
2014-10-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/19/10/16223 |
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| author | Abdellah Messoussi Lucile Peyronnet Clémence Feneyrolles Gwénaël Chevé Khalid Bougrin Aziz Yasri |
| author_facet | Abdellah Messoussi Lucile Peyronnet Clémence Feneyrolles Gwénaël Chevé Khalid Bougrin Aziz Yasri |
| author_sort | Abdellah Messoussi |
| collection | DOAJ |
| description | Structural elucidation of the active (DFG-Asp in) and inactive (DFG-Asp out) states of the TAM family of receptor tyrosine kinases is required for future development of TAM inhibitors as drugs. Herein we report a computational study on each of the three TAM members Tyro-3, Axl and Mer. DFG-Asp in and DFG-Asp out homology models of each one were built based on the X-ray structure of c-Met kinase, an enzyme with a closely related sequence. Structural validation and in silico screening enabled identification of critical amino acids for ligand binding within the active site of each DFG-Asp in and DFG-Asp out model. The position and nature of amino acids that differ among Tyro-3, Axl and Mer, and the potential role of these residues in the design of selective TAM ligands, are discussed. |
| first_indexed | 2024-12-10T12:30:33Z |
| format | Article |
| id | doaj.art-3c0a960b827e4eabbcc1bf0bb5117d08 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-10T12:30:33Z |
| publishDate | 2014-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-3c0a960b827e4eabbcc1bf0bb5117d082022-12-22T01:48:50ZengMDPI AGMolecules1420-30492014-10-011910162231623910.3390/molecules191016223molecules191016223Structural Elucidation of the DFG-Asp in and DFG-Asp out States of TAM Kinases and Insight into the Selectivity of Their InhibitorsAbdellah Messoussi0Lucile Peyronnet1Clémence Feneyrolles2Gwénaël Chevé3Khalid Bougrin4Aziz Yasri5OriBase Pharma, Parc Euromedecine, Cap Gamma, 1682, rue de la Valsière, 34189 Montpellier, FranceOriBase Pharma, Parc Euromedecine, Cap Gamma, 1682, rue de la Valsière, 34189 Montpellier, FranceOriBase Pharma, Parc Euromedecine, Cap Gamma, 1682, rue de la Valsière, 34189 Montpellier, FranceOriBase Pharma, Parc Euromedecine, Cap Gamma, 1682, rue de la Valsière, 34189 Montpellier, FranceLaboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, URAC23, Université Mohammed V, Faculté des Sciences B.P., 1014 Rabat, MoroccoOriBase Pharma, Parc Euromedecine, Cap Gamma, 1682, rue de la Valsière, 34189 Montpellier, FranceStructural elucidation of the active (DFG-Asp in) and inactive (DFG-Asp out) states of the TAM family of receptor tyrosine kinases is required for future development of TAM inhibitors as drugs. Herein we report a computational study on each of the three TAM members Tyro-3, Axl and Mer. DFG-Asp in and DFG-Asp out homology models of each one were built based on the X-ray structure of c-Met kinase, an enzyme with a closely related sequence. Structural validation and in silico screening enabled identification of critical amino acids for ligand binding within the active site of each DFG-Asp in and DFG-Asp out model. The position and nature of amino acids that differ among Tyro-3, Axl and Mer, and the potential role of these residues in the design of selective TAM ligands, are discussed.http://www.mdpi.com/1420-3049/19/10/16223tyrosine kinaseTAM kinase familyhomology modelkinase selectivity |
| spellingShingle | Abdellah Messoussi Lucile Peyronnet Clémence Feneyrolles Gwénaël Chevé Khalid Bougrin Aziz Yasri Structural Elucidation of the DFG-Asp in and DFG-Asp out States of TAM Kinases and Insight into the Selectivity of Their Inhibitors Molecules tyrosine kinase TAM kinase family homology model kinase selectivity |
| title | Structural Elucidation of the DFG-Asp in and DFG-Asp out States of TAM Kinases and Insight into the Selectivity of Their Inhibitors |
| title_full | Structural Elucidation of the DFG-Asp in and DFG-Asp out States of TAM Kinases and Insight into the Selectivity of Their Inhibitors |
| title_fullStr | Structural Elucidation of the DFG-Asp in and DFG-Asp out States of TAM Kinases and Insight into the Selectivity of Their Inhibitors |
| title_full_unstemmed | Structural Elucidation of the DFG-Asp in and DFG-Asp out States of TAM Kinases and Insight into the Selectivity of Their Inhibitors |
| title_short | Structural Elucidation of the DFG-Asp in and DFG-Asp out States of TAM Kinases and Insight into the Selectivity of Their Inhibitors |
| title_sort | structural elucidation of the dfg asp in and dfg asp out states of tam kinases and insight into the selectivity of their inhibitors |
| topic | tyrosine kinase TAM kinase family homology model kinase selectivity |
| url | http://www.mdpi.com/1420-3049/19/10/16223 |
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