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

Molecules

Abdellah Messoussi²  Lucile Peyronnet²  Clémence Feneyrolles²  Gwénaël Chevé²  Khalid Bougrin¹  Aziz Yasri² 

[1] Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, URAC23, Université Mohammed V, Faculté des Sciences B.P., 1014 Rabat, Morocco; E-Mail:;OriBase Pharma, Parc Euromedecine, Cap Gamma, 1682, rue de la Valsière, 34189 Montpellier, France; E-Mails:

关键词: tyrosine kinase;    TAM kinase family;    homology model;    kinase selectivity;   

DOI  :  10.3390/molecules191016223

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.