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| | <StructureSection load='7aax' size='340' side='right'caption='[[7aax]], [[Resolution|resolution]] 1.76Å' scene=''> | | <StructureSection load='7aax' size='340' side='right'caption='[[7aax]], [[Resolution|resolution]] 1.76Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7aax]] is a 1 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=7AAX OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7AAX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7aax]] is a 1 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=7AAX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AAX 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=R6H:~{N}-[4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluoranyl-phenyl]-4-ethoxy-1-(4-fluoranyl-2-methyl-phenyl)pyrazole-3-carboxamide'>R6H</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]] 1.762Å</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='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=R6H:~{N}-[4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluoranyl-phenyl]-4-ethoxy-1-(4-fluoranyl-2-methyl-phenyl)pyrazole-3-carboxamide'>R6H</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=7aax FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7aax OCA], [https://pdbe.org/7aax PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7aax RCSB], [https://www.ebi.ac.uk/pdbsum/7aax PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7aax ProSAT]</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=7aax FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7aax OCA], [http://pdbe.org/7aax PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7aax RCSB], [http://www.ebi.ac.uk/pdbsum/7aax PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7aax 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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| | </div> | | </div> |
| | <div class="pdbe-citations 7aax" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 7aax" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Receptor protein-tyrosine kinase]]
| + | [[Category: McCoull W]] |
| - | [[Category: McCoull, W]] | + | [[Category: Nissink JWM]] |
| - | [[Category: Nissink, J W.M]] | + | [[Category: Overman RC]] |
| - | [[Category: Overman, R C]] | + | [[Category: Pflug A]] |
| - | [[Category: Pflug, A]] | + | [[Category: Rawlins PB]] |
| - | [[Category: Rawlins, P B]] | + | [[Category: Schimpl M]] |
| - | [[Category: Schimpl, M]] | + | [[Category: Truman C]] |
| - | [[Category: Truman, C]] | + | [[Category: Underwood E]] |
| - | [[Category: Underwood, E]] | + | [[Category: Warwicker J]] |
| - | [[Category: Warwicker, J]] | + | [[Category: Winter-Holt J]] |
| - | [[Category: Winter-Holt, J]] | + | |
| - | [[Category: Structure-based drug design]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Type 2 inhibitor]]
| + | |
| - | [[Category: Tyrosine kinase inhibitor]]
| + | |
| 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
The activation loop (A-loop) plays a key role in regulating the catalytic activity of protein kinases. Phosphorylation in this region enhances the phosphoryl transfer rate of the kinase domain and increases its affinity for ATP. Furthermore, the A-loop possesses autoinhibitory functions in some kinases, where it collapses onto the protein surface and blocks substrate binding when unphosphorylated. Due to its flexible nature, the A-loop is usually disordered and untraceable in kinase domain crystal structures. The resulting lack of structural information is regrettable as it impedes the design of drug A-loop contacts, which have proven favourable in multiple cases. Here we characterize the binding with A-loop engagement between type 1.5 kinase inhibitor 'example 172' (EX172) and Mer tyrosine kinase (MerTK). With the help of crystal structures and binding kinetics we portray how the recruitment of the A-loop elicits a two-step binding mechanism which results in a drug-target complex characterized by high affinity and long residence time. In addition, the type 1.5 compound possesses excellent kinome selectivity and a remarkable preference for the phosphorylated over the dephosphorylated form of MerTK. We discuss these unique characteristics in the context of known type 1 and type 2 inhibitors and highlight opportunities for future kinase inhibitor design.
A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding.,Pflug A, Schimpl M, Nissink JWM, Overman RC, Rawlins PB, Truman C, Underwood E, Warwicker J, Winter-Holt JJ, McCoull W Biochem J. 2020 Oct 29. pii: 226803. doi: 10.1042/BCJ20200735. PMID:33119085[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
- ↑ Pflug A, Schimpl M, Nissink JWM, Overman RC, Rawlins PB, Truman C, Underwood E, Warwicker J, Winter-Holt JJ, McCoull W. A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding. Biochem J. 2020 Oct 29. pii: 226803. doi: 10.1042/BCJ20200735. PMID:33119085 doi:http://dx.doi.org/10.1042/BCJ20200735
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