5k0x

From Proteopedia

(Difference between revisions)

Revision as of 09:13, 25 June 2020

Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC2541

Structural highlights

5k0x 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:	5k0k
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

Macrocycles have attracted significant attention in drug discovery recently. In fact, a few de novo designed macrocyclic kinase inhibitors are currently in clinical trials with good potency and selectivity for their intended target. In this study, we successfully engaged a structure-based drug design approach to discover macrocyclic pyrimidines as potent Mer tyrosine kinase (MerTK)-specific inhibitors. An enzyme-linked immunosorbent assay (ELISA) in 384-well format was employed to evaluate the inhibitory activity of macrocycles in a cell-based assay assessing tyrosine phosphorylation of MerTK. Through structure-activity relationship (SAR) studies, analogue 11 [UNC2541; (S)-7-amino-N-(4-fluorobenzyl)-8-oxo-2,9,16-triaza-1(2,4)-pyrimidinacyclohexadeca phane-1-carboxamide] was identified as a potent and MerTK-specific inhibitor that exhibits sub-micromolar inhibitory activity in the cell-based ELISA. In addition, an X-ray structure of MerTK protein in complex with 11 was resolved to show that these macrocycles bind in the MerTK ATP pocket.

Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors.,McIver AL, Zhang W, Liu Q, Jiang X, Stashko MA, Nichols J, Miley MJ, Norris-Drouin J, Machius M, DeRyckere D, Wood E, Graham DK, Earp HS, Kireev D, Frye SV, Wang X ChemMedChem. 2017 Feb 3;12(3):207-213. doi: 10.1002/cmdc.201600589. Epub 2017 Jan, 9. PMID:28032464^[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
↑ McIver AL, Zhang W, Liu Q, Jiang X, Stashko MA, Nichols J, Miley MJ, Norris-Drouin J, Machius M, DeRyckere D, Wood E, Graham DK, Earp HS, Kireev D, Frye SV, Wang X. Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors. ChemMedChem. 2017 Feb 3;12(3):207-213. doi: 10.1002/cmdc.201600589. Epub 2017 Jan, 9. PMID:28032464 doi:http://dx.doi.org/10.1002/cmdc.201600589

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/5k0x"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC2541==
-<StructureSection load='5k0x' size='340' side='right' caption='[[5k0x]], [[Resolution|resolution]] 2.23&Aring;' scene=''>
+<StructureSection load='5k0x' size='340' side='right'caption='[[5k0x]], [[Resolution|resolution]] 2.23&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5k0x]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K0X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5K0X FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5k0x]] 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=5K0X OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5K0X FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=K0X:(7S)-7-AMINO-N-[(4-FLUOROPHENYL)METHYL]-8-OXO-2,9,16,18,21-PENTAAZABICYCLO[15.3.1]HENICOSA-1(21),17,19-TRIENE-20-CARBOXAMIDE'>K0X</scene></td></tr>
+</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=K0X:(7S)-7-AMINO-N-[(4-FLUOROPHENYL)METHYL]-8-OXO-2,9,16,18,21-PENTAAZABICYCLO[15.3.1]HENICOSA-1(21),17,19-TRIENE-20-CARBOXAMIDE'>K0X</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5k0k|5k0k]]</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=5k0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k0x OCA], [http://pdbe.org/5k0x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5k0x RCSB], [http://www.ebi.ac.uk/pdbsum/5k0x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5k0x 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=5k0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k0x OCA], [http://pdbe.org/5k0x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5k0x RCSB], [http://www.ebi.ac.uk/pdbsum/5k0x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5k0x ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 22: / Line 23: @@
 </div>
 <div class="pdbe-citations 5k0x" 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: DeRyckere, D]]

5k0x

From Proteopedia

Revision as of 09:13, 25 June 2020

Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC2541

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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