title: Structural elucidation of the DFG-Asp in and DFG-Asp out states of TAM kinases and insight into the selectivity of their inhibitors.
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.
authors.affiliation: OriBase Pharma, Parc Euromedecine, Cap Gamma, 1682, rue de la Valsière, 34189 Montpellier, France. khalid.bougrin@smct-ma.com.
authors.forename: Abdellah
authors.initials: A
authors.lastname: Messoussi
authors.affiliation: OriBase Pharma, Parc Euromedecine, Cap Gamma, 1682, rue de la Valsière, 34189 Montpellier, France. lpeyronnet@oribase-pharma.com.
authors.forename: Lucile
authors.initials: L
authors.lastname: Peyronnet
authors.affiliation: OriBase Pharma, Parc Euromedecine, Cap Gamma, 1682, rue de la Valsière, 34189 Montpellier, France. cfeneyrolles@oribase-pharma.com.
authors.forename: Clémence
authors.initials: C
authors.lastname: Feneyrolles
authors.affiliation: OriBase Pharma, Parc Euromedecine, Cap Gamma, 1682, rue de la Valsière, 34189 Montpellier, France. gcheve@oribase-pharma.com.
authors.forename: Gwénaël
authors.initials: G
authors.lastname: Chevé
authors.affiliation: Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, URAC23, Université Mohammed V, Faculté des Sciences B.P., 1014 Rabat, Morocco. khalid.bougrin@smct-ma.com.
authors.forename: Khalid
authors.initials: K
authors.lastname: Bougrin
authors.affiliation: OriBase Pharma, Parc Euromedecine, Cap Gamma, 1682, rue de la Valsière, 34189 Montpellier, France. ayasri@oribase-pharma.com.
authors.forename: Aziz
authors.initials: A
authors.lastname: Yasri
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010770:Phosphotransferases; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D016415:Sequence Alignment
chemical_list: D047428:Protein Kinase Inhibitors; D010770:Phosphotransferases; D020794:Receptor Protein-Tyrosine Kinases