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| - | [[Image:2p0c.jpg|left|200px]]<br /><applet load="2p0c" size="350" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="2p0c, resolution 2.40Å" /> | |
| - | '''Catalytic Domain of the Proto-oncogene Tyrosine-protein Kinase MER'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Catalytic Domain of the Proto-oncogene Tyrosine-protein Kinase MER== |
| - | A human B-lymphoblastoid lambda gt11 expression library was screened using, anti-phosphotyrosine antibodies yielding complementary DNAs encoding, active tyrosine kinases. The resulting clones were used to obtain the, sequence of a novel 984 amino acid transmembrane tyrosine kinase. Analysis, of the complementary DNA revealed extracellular immunoglobulin and, fibronectin type III domains and the unusual kinase signature sequence, KWIAIES; all are characteristic of the axl family of tyrosine kinases. The, novel tyrosine kinase was not expressed in normal B- and T-lymphocytes, but, unlike axl, was expressed in numerous neoplastic B- and T-cell lines., Transcripts for the novel receptor-like tyrosine kinase were detected in, normal peripheral blood monocytes and bone marrow. One alternatively, spliced transcript was detected which contained an insert in the membrane, proximal region that could encode for a truncated, soluble receptor., Sequence comparison shows that the kinase may be the human protooncogene, for the recently isolated chicken retroviral oncogene v-ryk (recently, renamed v-eyk), a truncated tyrosine kinase whose expression by retroviral, infection produced sarcomas in chickens. The intracellular domain of the, human kinase shows 83% similarity and 71% identity to v-ryk. Since the ryk, designation has been used to name another tyrosine kinase and an analysis, of RNA expression demonstrated that this novel human kinase is expressed, in monocytes and tissues of epithelial and reproductive origin, we have, designated our novel protooncogene c-mer.
| + | <StructureSection load='2p0c' size='340' side='right'caption='[[2p0c]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[2p0c]] 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=2P0C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2P0C FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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=2p0c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2p0c OCA], [https://pdbe.org/2p0c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2p0c RCSB], [https://www.ebi.ac.uk/pdbsum/2p0c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2p0c ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == 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> |
| | + | == 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> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/p0/2p0c_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2p0c ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | The mammalian ortholog of the retroviral oncogene v-Eyk, and a receptor tyrosine kinase upstream of antiapoptotic and transforming signals, Mer (MerTK) is a mediator of the phagocytic process, being involved in retinal and immune cell clearance and platelet aggregation. Mer knockout mice are viable and are protected from epinephrine-induced pulmonary thromboembolism and ferric chloride-induced thrombosis. Mer overexpression, on the other hand, is associated with numerous carcinomas. Although Mer adaptor proteins and signaling pathways have been identified, it remains unclear how Mer initiates phagocytosis. When bound to its nucleotide cofactor, the high-resolution structure of Mer shows an autoinhibited alphaC-Glu-out conformation with insertion of an activation loop residue into the active site. Mer complexed with compound-52 (C52: 2-(2-hydroxyethylamino)-6-(3-chloroanilino)-9-isopropylpurine), a ligand identified from a focused library, retains its DFG-Asp-in and alphaC-Glu-out conformation, but acquires other conformational changes. The alphaC helix and DFGL region is closer to the hinge region and the ethanolamine moiety of C52 binds in the groove formed between Leu593 and Val601 of the P-loop, causing a compression of the active site pocket. These conformational states reveal the mechanisms of autoinhibition, the pathophysiological basis of disease-causing mutations, and a platform for the development of chemical probes. |
| | | | |
| - | ==About this Structure==
| + | Structural insights into the inhibited states of the Mer receptor tyrosine kinase.,Huang X, Finerty P Jr, Walker JR, Butler-Cole C, Vedadi M, Schapira M, Parker SA, Turk BE, Thompson DA, Dhe-Paganon S J Struct Biol. 2009 Feb;165(2):88-96. Epub 2008 Nov 5. PMID:19028587<ref>PMID:19028587</ref> |
| - | 2P0C is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MG:'>MG</scene>, <scene name='pdbligand=ANP:'>ANP</scene> and <scene name='pdbligand=BME:'>BME</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2P0C OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Cloning and mRNA expression analysis of a novel human protooncogene, c-mer., Graham DK, Dawson TL, Mullaney DL, Snodgrass HR, Earp HS, Cell Growth Differ. 1994 Jun;5(6):647-57. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=8086340 8086340]
| + | </div> |
| - | [[Category: Homo sapiens]]
| + | <div class="pdbe-citations 2p0c" style="background-color:#fffaf0;"></div> |
| - | [[Category: Receptor protein-tyrosine kinase]]
| + | |
| - | [[Category: Single protein]]
| + | |
| - | [[Category: Arrowsmith, C.H.]]
| + | |
| - | [[Category: Bochkarev, A.]]
| + | |
| - | [[Category: Dhe-Paganon, S.]]
| + | |
| - | [[Category: Edwards, A.M.]]
| + | |
| - | [[Category: Huang, X.]]
| + | |
| - | [[Category: Jr., P.J.Finerty.]]
| + | |
| - | [[Category: SGC, Structural.Genomics.Consortium.]]
| + | |
| - | [[Category: Sundstrom, M.]]
| + | |
| - | [[Category: Walker, J.R.]]
| + | |
| - | [[Category: Weigelt, J.]]
| + | |
| - | [[Category: ANP]]
| + | |
| - | [[Category: BME]]
| + | |
| - | [[Category: MG]]
| + | |
| - | [[Category: atp-binding]]
| + | |
| - | [[Category: disease mutation]]
| + | |
| - | [[Category: glycoprotein]]
| + | |
| - | [[Category: kinase]]
| + | |
| - | [[Category: nucleotide-binding]]
| + | |
| - | [[Category: phosphorylation]]
| + | |
| - | [[Category: proto-oncogene]]
| + | |
| - | [[Category: receptor]]
| + | |
| - | [[Category: retinitis pigmentosa]]
| + | |
| - | [[Category: sensory transduction]]
| + | |
| - | [[Category: sgc]]
| + | |
| - | [[Category: signal]]
| + | |
| - | [[Category: structural genomics]]
| + | |
| - | [[Category: structural genomics consortium]]
| + | |
| - | [[Category: transferase]]
| + | |
| - | [[Category: tyrosine-protein kinase]]
| + | |
| - | [[Category: vision]]
| + | |
| | | | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 15:21:41 2008''
| + | ==See Also== |
| | + | *[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | + | [[Category: Large Structures]] |
| | + | [[Category: Arrowsmith CH]] |
| | + | [[Category: Bochkarev A]] |
| | + | [[Category: Dhe-Paganon S]] |
| | + | [[Category: Edwards AM]] |
| | + | [[Category: Finerty Jr PJ]] |
| | + | [[Category: Huang X]] |
| | + | [[Category: Sundstrom M]] |
| | + | [[Category: Walker JR]] |
| | + | [[Category: Weigelt J]] |
| 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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The mammalian ortholog of the retroviral oncogene v-Eyk, and a receptor tyrosine kinase upstream of antiapoptotic and transforming signals, Mer (MerTK) is a mediator of the phagocytic process, being involved in retinal and immune cell clearance and platelet aggregation. Mer knockout mice are viable and are protected from epinephrine-induced pulmonary thromboembolism and ferric chloride-induced thrombosis. Mer overexpression, on the other hand, is associated with numerous carcinomas. Although Mer adaptor proteins and signaling pathways have been identified, it remains unclear how Mer initiates phagocytosis. When bound to its nucleotide cofactor, the high-resolution structure of Mer shows an autoinhibited alphaC-Glu-out conformation with insertion of an activation loop residue into the active site. Mer complexed with compound-52 (C52: 2-(2-hydroxyethylamino)-6-(3-chloroanilino)-9-isopropylpurine), a ligand identified from a focused library, retains its DFG-Asp-in and alphaC-Glu-out conformation, but acquires other conformational changes. The alphaC helix and DFGL region is closer to the hinge region and the ethanolamine moiety of C52 binds in the groove formed between Leu593 and Val601 of the P-loop, causing a compression of the active site pocket. These conformational states reveal the mechanisms of autoinhibition, the pathophysiological basis of disease-causing mutations, and a platform for the development of chemical probes.
Structural insights into the inhibited states of the Mer receptor tyrosine kinase.,Huang X, Finerty P Jr, Walker JR, Butler-Cole C, Vedadi M, Schapira M, Parker SA, Turk BE, Thompson DA, Dhe-Paganon S J Struct Biol. 2009 Feb;165(2):88-96. Epub 2008 Nov 5. PMID:19028587[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
- ↑ Huang X, Finerty P Jr, Walker JR, Butler-Cole C, Vedadi M, Schapira M, Parker SA, Turk BE, Thompson DA, Dhe-Paganon S. Structural insights into the inhibited states of the Mer receptor tyrosine kinase. J Struct Biol. 2009 Feb;165(2):88-96. Epub 2008 Nov 5. PMID:19028587 doi:10.1016/j.jsb.2008.10.003
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