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5k0k

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Revision as of 09:12, 25 June 2020

Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC2434

Structural highlights

5k0k is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	5k0x
Gene:	MERTK, MER (HUMAN)
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

Mer tyrosine kinase (MerTK) is aberrantly elevated in various tumor cells and has a normal anti-inflammatory role in the innate immune system. Inhibition of MerTK may provide dual effects against these MerTK-expressing tumors through reducing cancer cell survival and redirecting the innate immune response. Recently, we have designed novel and potent macrocyclic pyrrolopyrimidines as MerTK inhibitors using a structure-based approach. The most active macrocycles had an EC50 below 40 nM in a cell-based MerTK phosphor-protein ELISA assay. The X-ray structure of macrocyclic analogue 3 complexed with MerTK was also resolved and demonstrated macrocycles binding in the ATP binding pocket of the MerTK protein as anticipated. In addition, the lead compound 16 (UNC3133) had a 1.6 h half-life and 16% oral bioavailability in a mouse PK study.

Design and Synthesis of Novel Macrocyclic Mer Tyrosine Kinase Inhibitors.,Wang X, Liu J, Zhang W, Stashko MA, Nichols J, Miley MJ, Norris-Drouin J, Chen Z, Machius M, DeRyckere D, Wood E, Graham DK, Earp HS, Kireev D, Frye SV ACS Med Chem Lett. 2016 Sep 13;7(12):1044-1049. eCollection 2016 Dec 8. PMID:27994735^[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
↑ Wang X, Liu J, Zhang W, Stashko MA, Nichols J, Miley MJ, Norris-Drouin J, Chen Z, Machius M, DeRyckere D, Wood E, Graham DK, Earp HS, Kireev D, Frye SV. Design and Synthesis of Novel Macrocyclic Mer Tyrosine Kinase Inhibitors. ACS Med Chem Lett. 2016 Sep 13;7(12):1044-1049. eCollection 2016 Dec 8. PMID:27994735 doi:http://dx.doi.org/10.1021/acsmedchemlett.6b00221

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/5k0k"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC2434==
-<StructureSection load='5k0k' size='340' side='right' caption='[[5k0k]], [[Resolution|resolution]] 2.54&Aring;' scene=''>
+<StructureSection load='5k0k' size='340' side='right'caption='[[5k0k]], [[Resolution|resolution]] 2.54&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5k0k]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K0K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5K0K FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5k0k]] 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=5K0K OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5K0K FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6Q1:15-{4-[(4-METHYLPIPERAZIN-1-YL)METHYL]PHENYL}-4,5,6,7,9,10,11,12-OCTAHYDRO-2,16-(AZENOMETHENO)PYRROLO[2,1-D][1,3,5,9]TETRAAZACYCLOTETRADECIN-8(3H)-ONE'>6Q1</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6Q1:15-{4-[(4-METHYLPIPERAZIN-1-YL)METHYL]PHENYL}-4,5,6,7,9,10,11,12-OCTAHYDRO-2,16-(AZENOMETHENO)PYRROLO[2,1-D][1,3,5,9]TETRAAZACYCLOTETRADECIN-8(3H)-ONE'>6Q1</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5k0x|5k0x]]</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='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=5k0k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k0k OCA], [http://pdbe.org/5k0k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5k0k RCSB], [http://www.ebi.ac.uk/pdbsum/5k0k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5k0k 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=5k0k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k0k OCA], [http://pdbe.org/5k0k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5k0k RCSB], [http://www.ebi.ac.uk/pdbsum/5k0k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5k0k ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 22: / Line 23: @@
 </div>
 <div class="pdbe-citations 5k0k" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Receptor protein-tyrosine kinase]]
 [[Category: Chen, Z]]

5k0k

From Proteopedia

Revision as of 09:12, 25 June 2020

Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC2434

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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