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| | <StructureSection load='5k0x' size='340' side='right'caption='[[5k0x]], [[Resolution|resolution]] 2.23Å' scene=''> | | <StructureSection load='5k0x' size='340' side='right'caption='[[5k0x]], [[Resolution|resolution]] 2.23Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5k0x]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K0X OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5K0X FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5k0x]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K0X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5K0X FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=K0X:(7S)-7-AMINO-N-[(4-FLUOROPHENYL)METHYL]-8-OXO-2,9,16,18,21-PENTAAZABICYCLO[15.3.1]HENICOSA-1(21),17,19-TRIENE-20-CARBOXAMIDE'>K0X</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.231Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5k0k|5k0k]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=K0X:(7S)-7-AMINO-N-[(4-FLUOROPHENYL)METHYL]-8-OXO-2,9,16,18,21-PENTAAZABICYCLO[15.3.1]HENICOSA-1(21),17,19-TRIENE-20-CARBOXAMIDE'>K0X</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MERTK, MER ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5k0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k0x OCA], [https://pdbe.org/5k0x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5k0x RCSB], [https://www.ebi.ac.uk/pdbsum/5k0x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5k0x ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5k0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k0x OCA], [http://pdbe.org/5k0x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5k0x RCSB], [http://www.ebi.ac.uk/pdbsum/5k0x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5k0x ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/MERTK_HUMAN MERTK_HUMAN]] Defects in MERTK are the cause of retinitis pigmentosa type 38 (RP38) [MIM:[http://omim.org/entry/613862 613862]]. RP38 is a retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well.<ref>PMID:11062461</ref> | + | [https://www.uniprot.org/uniprot/MERTK_HUMAN MERTK_HUMAN] Defects in MERTK are the cause of retinitis pigmentosa type 38 (RP38) [MIM:[https://omim.org/entry/613862 613862]. RP38 is a retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well.<ref>PMID:11062461</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MERTK_HUMAN MERTK_HUMAN]] Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including LGALS3, TUB, TULP1 or GAS6. Regulates many physiological processes including cell survival, migration, differentiation, and phagocytosis of apoptotic cells (efferocytosis). Ligand binding at the cell surface induces autophosphorylation of MERTK on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with GRB2 or PLCG2 and induces phosphorylation of MAPK1, MAPK2, FAK/PTK2 or RAC1. MERTK signaling plays a role in various processes such as macrophage clearance of apoptotic cells, platelet aggregation, cytoskeleton reorganization and engulfment. Functions in the retinal pigment epithelium (RPE) as a regulator of rod outer segments fragments phagocytosis. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3.<ref>PMID:17005688</ref> | + | [https://www.uniprot.org/uniprot/MERTK_HUMAN MERTK_HUMAN] Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including LGALS3, TUB, TULP1 or GAS6. Regulates many physiological processes including cell survival, migration, differentiation, and phagocytosis of apoptotic cells (efferocytosis). Ligand binding at the cell surface induces autophosphorylation of MERTK on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with GRB2 or PLCG2 and induces phosphorylation of MAPK1, MAPK2, FAK/PTK2 or RAC1. MERTK signaling plays a role in various processes such as macrophage clearance of apoptotic cells, platelet aggregation, cytoskeleton reorganization and engulfment. Functions in the retinal pigment epithelium (RPE) as a regulator of rod outer segments fragments phagocytosis. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3.<ref>PMID:17005688</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Receptor protein-tyrosine kinase]]
| + | [[Category: DeRyckere D]] |
| - | [[Category: DeRyckere, D]] | + | [[Category: Earp HS]] |
| - | [[Category: Earp, H S]] | + | [[Category: Frye SV]] |
| - | [[Category: Frye, S V]] | + | [[Category: Graham DK]] |
| - | [[Category: Graham, D K]] | + | [[Category: Jiang X]] |
| - | [[Category: Jiang, X]] | + | [[Category: Kireev D]] |
| - | [[Category: Kireev, D]] | + | [[Category: Liu Q]] |
| - | [[Category: Liu, Q]] | + | [[Category: Machius M]] |
| - | [[Category: Machius, M]] | + | [[Category: McIver AL]] |
| - | [[Category: McIver, A L]] | + | [[Category: Miley MJ]] |
| - | [[Category: Miley, M J]] | + | [[Category: Nichols J]] |
| - | [[Category: Nichols, J]] | + | [[Category: Norris-Drouin J]] |
| - | [[Category: Norris-Drouin, J]] | + | [[Category: Stashko MA]] |
| - | [[Category: Stashko, M A]] | + | [[Category: Wang X]] |
| - | [[Category: Wang, X]] | + | [[Category: Wood E]] |
| - | [[Category: Wood, E]] | + | [[Category: Zhang W]] |
| - | [[Category: Zhang, W]] | + | |
| - | [[Category: Drug design]]
| + | |
| - | [[Category: Fibrinolytic agent]]
| + | |
| - | [[Category: Macrocyclic]]
| + | |
| - | [[Category: Protein kinase inhibitor]]
| + | |
| - | [[Category: Proto-oncogene protein]]
| + | |
| - | [[Category: Pyrimidine]]
| + | |
| - | [[Category: Structure-activity relationship]]
| + | |
| - | [[Category: Thrombosis]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Disease
MERTK_HUMAN Defects in MERTK are the cause of retinitis pigmentosa type 38 (RP38) [MIM:613862. RP38 is a retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well.[1]
Function
MERTK_HUMAN Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including LGALS3, TUB, TULP1 or GAS6. Regulates many physiological processes including cell survival, migration, differentiation, and phagocytosis of apoptotic cells (efferocytosis). Ligand binding at the cell surface induces autophosphorylation of MERTK on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with GRB2 or PLCG2 and induces phosphorylation of MAPK1, MAPK2, FAK/PTK2 or RAC1. MERTK signaling plays a role in various processes such as macrophage clearance of apoptotic cells, platelet aggregation, cytoskeleton reorganization and engulfment. Functions in the retinal pigment epithelium (RPE) as a regulator of rod outer segments fragments phagocytosis. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3.[2]
Publication Abstract from PubMed
Macrocycles have attracted significant attention in drug discovery recently. In fact, a few de novo designed macrocyclic kinase inhibitors are currently in clinical trials with good potency and selectivity for their intended target. In this study, we successfully engaged a structure-based drug design approach to discover macrocyclic pyrimidines as potent Mer tyrosine kinase (MerTK)-specific inhibitors. An enzyme-linked immunosorbent assay (ELISA) in 384-well format was employed to evaluate the inhibitory activity of macrocycles in a cell-based assay assessing tyrosine phosphorylation of MerTK. Through structure-activity relationship (SAR) studies, analogue 11 [UNC2541; (S)-7-amino-N-(4-fluorobenzyl)-8-oxo-2,9,16-triaza-1(2,4)-pyrimidinacyclohexadeca phane-1-carboxamide] was identified as a potent and MerTK-specific inhibitor that exhibits sub-micromolar inhibitory activity in the cell-based ELISA. In addition, an X-ray structure of MerTK protein in complex with 11 was resolved to show that these macrocycles bind in the MerTK ATP pocket.
Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors.,McIver AL, Zhang W, Liu Q, Jiang X, Stashko MA, Nichols J, Miley MJ, Norris-Drouin J, Machius M, DeRyckere D, Wood E, Graham DK, Earp HS, Kireev D, Frye SV, Wang X ChemMedChem. 2017 Feb 3;12(3):207-213. doi: 10.1002/cmdc.201600589. Epub 2017 Jan, 9. PMID:28032464[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gal A, Li Y, Thompson DA, Weir J, Orth U, Jacobson SG, Apfelstedt-Sylla E, Vollrath D. Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat Genet. 2000 Nov;26(3):270-1. PMID:11062461 doi:10.1038/81555
- ↑ Shimojima M, Takada A, Ebihara H, Neumann G, Fujioka K, Irimura T, Jones S, Feldmann H, Kawaoka Y. Tyro3 family-mediated cell entry of Ebola and Marburg viruses. J Virol. 2006 Oct;80(20):10109-16. PMID:17005688 doi:80/20/10109
- ↑ McIver AL, Zhang W, Liu Q, Jiang X, Stashko MA, Nichols J, Miley MJ, Norris-Drouin J, Machius M, DeRyckere D, Wood E, Graham DK, Earp HS, Kireev D, Frye SV, Wang X. Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors. ChemMedChem. 2017 Feb 3;12(3):207-213. doi: 10.1002/cmdc.201600589. Epub 2017 Jan, 9. PMID:28032464 doi:http://dx.doi.org/10.1002/cmdc.201600589
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