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4mh7

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Revision as of 10:38, 11 August 2016

Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC1896

Structural highlights

4mh7 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	2poc, 3tcp, 2brb, 3bpr, 4m3q, 4mha
Activity:	Receptor protein-tyrosine kinase, with EC number 2.7.10.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 role of Mer kinase in regulating the second phase of platelet activation generates an opportunity to use Mer inhibitors for preventing thrombosis with diminished likelihood for bleeding as compared to current therapies. Toward this end, we have discovered a novel, Mer kinase specific substituted-pyrimidine scaffold using a structure-based drug design and a pseudo ring replacement strategy. The cocrystal structure of Mer with two compounds (7 and 22) possessing distinct activity have been determined. Subsequent SAR studies identified compound 23 (UNC2881) as a lead compound for in vivo evaluation. When applied to live cells, 23 inhibits steady-state Mer kinase phosphorylation with an IC50 value of 22 nM. Treatment with 23 is also sufficient to block EGF-mediated stimulation of a chimeric receptor containing the intracellular domain of Mer fused to the extracellular domain of EGFR. In addition, 23 potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathologic thrombosis.

Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis.,Zhang W, McIver AL, Stashko MA, DeRyckere D, Branchford BR, Hunter D, Kireev D, Miley MJ, Norris-Drouin J, Stewart WM, Lee M, Sather S, Zhou Y, Di Paola JA, Machius M, Janzen WP, Earp HS, Graham DK, Frye SV, Wang X J Med Chem. 2013 Dec 12;56(23):9693-700. doi: 10.1021/jm4013888. Epub 2013 Nov, 20. PMID:24219778^[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
↑ Zhang W, McIver AL, Stashko MA, DeRyckere D, Branchford BR, Hunter D, Kireev D, Miley MJ, Norris-Drouin J, Stewart WM, Lee M, Sather S, Zhou Y, Di Paola JA, Machius M, Janzen WP, Earp HS, Graham DK, Frye SV, Wang X. Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis. J Med Chem. 2013 Dec 12;56(23):9693-700. doi: 10.1021/jm4013888. Epub 2013 Nov, 20. PMID:24219778 doi:http://dx.doi.org/10.1021/jm4013888

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4mh7"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC1896==
 <StructureSection load='4mh7' size='340' side='right' caption='[[4mh7]], [[Resolution|resolution]] 2.51&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2poc|2poc]], [[3tcp|3tcp]], [[2brb|2brb]], [[3bpr|3bpr]], [[4m3q|4m3q]], [[4mha|4mha]]</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4mh7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mh7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mh7 RCSB], [http://www.ebi.ac.uk/pdbsum/4mh7 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4mh7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mh7 OCA], [http://pdbe.org/4mh7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4mh7 RCSB], [http://www.ebi.ac.uk/pdbsum/4mh7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4mh7 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 21: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4mh7" style="background-color:#fffaf0;"></div>
 ==See Also==

4mh7

From Proteopedia

Revision as of 10:38, 11 August 2016

Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC1896

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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