|
|
| Line 3: |
Line 3: |
| | <StructureSection load='7oam' size='340' side='right'caption='[[7oam]], [[Resolution|resolution]] 2.65Å' scene=''> | | <StructureSection load='7oam' size='340' side='right'caption='[[7oam]], [[Resolution|resolution]] 2.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7oam]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OAM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OAM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7oam]] 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=7OAM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OAM FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=V6H:2-[[2,5-bis(fluoranyl)phenyl]methylamino]-4-(cyclopentylamino)-N-[3-(2-oxidanylidenepyrrolidin-1-yl)propyl]pyrimidine-5-carboxamide'>V6H</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]] 2.65Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MERTK, MER ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=V6H:2-[[2,5-bis(fluoranyl)phenyl]methylamino]-4-(cyclopentylamino)-N-[3-(2-oxidanylidenepyrrolidin-1-yl)propyl]pyrimidine-5-carboxamide'>V6H</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=7oam FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7oam OCA], [https://pdbe.org/7oam PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7oam RCSB], [https://www.ebi.ac.uk/pdbsum/7oam PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7oam ProSAT]</span></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=7oam FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7oam OCA], [https://pdbe.org/7oam PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7oam RCSB], [https://www.ebi.ac.uk/pdbsum/7oam PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7oam ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[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>
| + | [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 == |
| - | [[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>
| + | [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 == |
| Line 26: |
Line 25: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Receptor protein-tyrosine kinase]]
| + | [[Category: Knapp S]] |
| - | [[Category: Knapp, S]] | + | [[Category: Russ N]] |
| - | [[Category: Russ, N]] | + | [[Category: Schroeder M]] |
| - | [[Category: Structural genomic]]
| + | |
| - | [[Category: Schroeder, M]] | + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Mertk]]
| + | |
| - | [[Category: Sgc]]
| + | |
| - | [[Category: Transferase]]
| + | |
| 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
CASK (Ca(2+)/calmodulin-dependent Ser/Thr kinase) is a member of the MAGUK (membrane-associated guanylate kinase) family that functions as neurexin kinases with roles implicated in neuronal synapses and trafficking. The lack of a canonical DFG motif, which is altered to GFG in CASK, led to the classification as a pseudokinase. However, functional studies revealed that CASK can still phosphorylate substrates in the absence of divalent metals. CASK dysfunction has been linked to many diseases, including colorectal cancer, Parkinson's disease, and X-linked mental retardation, suggesting CASK as a potential drug target. Here, we exploited structure-based design for the development of highly potent and selective CASK inhibitors based on 2,4-diaminopyrimidine-5-carboxamides targeting an unusual pocket created by the GFG motif. The presented inhibitor design offers a more general strategy for the development of pseudokinase ligands that harbor unusual sequence motifs. It also provides a first chemical probe for studying the biological roles of CASK.
Design and Development of a Chemical Probe for Pseudokinase Ca(2+)/calmodulin-Dependent Ser/Thr Kinase.,Russ N, Schroder M, Berger BT, Mandel S, Aydogan Y, Mauer S, Pohl C, Drewry DH, Chaikuad A, Muller S, Knapp S J Med Chem. 2021 Oct 14;64(19):14358-14376. doi: 10.1021/acs.jmedchem.1c00845., Epub 2021 Sep 20. PMID:34543009[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Russ N, Schroder M, Berger BT, Mandel S, Aydogan Y, Mauer S, Pohl C, Drewry DH, Chaikuad A, Muller S, Knapp S. Design and Development of a Chemical Probe for Pseudokinase Ca(2+)/calmodulin-Dependent Ser/Thr Kinase. J Med Chem. 2021 Oct 14;64(19):14358-14376. doi: 10.1021/acs.jmedchem.1c00845., Epub 2021 Sep 20. PMID:34543009 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c00845
|
