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Article

Structural Elucidation of the DFG-Asp in and DFG-Asp out States of TAM Kinases and Insight into the Selectivity of Their Inhibitors

by
Abdellah Messoussi
1,2,
Lucile Peyronnet
1,
Clémence Feneyrolles
1,
Gwénaël Chevé
1,
Khalid Bougrin
2 and
Aziz Yasri
1,*
1
OriBase Pharma, Parc Euromedecine, Cap Gamma, 1682, rue de la Valsière, 34189 Montpellier, France
2
Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, URAC23, Université Mohammed V, Faculté des Sciences B.P., 1014 Rabat, Morocco
*
Author to whom correspondence should be addressed.
Molecules 2014, 19(10), 16223-16239; https://doi.org/10.3390/molecules191016223
Submission received: 31 July 2014 / Revised: 24 September 2014 / Accepted: 26 September 2014 / Published: 10 October 2014
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
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Abstract

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.
Keywords: tyrosine kinase; TAM kinase family; homology model; kinase selectivity tyrosine kinase; TAM kinase family; homology model; kinase selectivity
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MDPI and ACS Style

Messoussi, A.; Peyronnet, L.; Feneyrolles, C.; Chevé, G.; Bougrin, K.; Yasri, A. Structural Elucidation of the DFG-Asp in and DFG-Asp out States of TAM Kinases and Insight into the Selectivity of Their Inhibitors. Molecules 2014, 19, 16223-16239. https://doi.org/10.3390/molecules191016223

AMA Style

Messoussi A, Peyronnet L, Feneyrolles C, Chevé G, Bougrin K, Yasri A. Structural Elucidation of the DFG-Asp in and DFG-Asp out States of TAM Kinases and Insight into the Selectivity of Their Inhibitors. Molecules. 2014; 19(10):16223-16239. https://doi.org/10.3390/molecules191016223

Chicago/Turabian Style

Messoussi, Abdellah, Lucile Peyronnet, Clémence Feneyrolles, Gwénaël Chevé, Khalid Bougrin, and Aziz Yasri. 2014. "Structural Elucidation of the DFG-Asp in and DFG-Asp out States of TAM Kinases and Insight into the Selectivity of Their Inhibitors" Molecules 19, no. 10: 16223-16239. https://doi.org/10.3390/molecules191016223

APA Style

Messoussi, A., Peyronnet, L., Feneyrolles, C., Chevé, G., Bougrin, K., & Yasri, A. (2014). Structural Elucidation of the DFG-Asp in and DFG-Asp out States of TAM Kinases and Insight into the Selectivity of Their Inhibitors. Molecules, 19(10), 16223-16239. https://doi.org/10.3390/molecules191016223

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