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Molecules 2014, 19(10), 16223-16239; doi:10.3390/molecules191016223

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

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.
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. View Full-Text
Keywords: tyrosine kinase; TAM kinase family; homology model; kinase selectivity tyrosine kinase; TAM kinase family; homology model; kinase selectivity
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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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.

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