4m3q

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Current revision (16:31, 20 September 2023) (edit) (undo)
 
(4 intermediate revisions not shown.)
Line 1: Line 1:
-
{{STRUCTURE_4m3q| PDB=4m3q | SCENE= }}
 
-
===Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC1917===
 
-
{{ABSTRACT_PUBMED_24195762}}
 
-
==Disease==
+
==Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC1917==
-
[[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>
+
<StructureSection load='4m3q' size='340' side='right'caption='[[4m3q]], [[Resolution|resolution]] 2.72&Aring;' scene=''>
 +
== Structural highlights ==
 +
<table><tr><td colspan='2'>[[4m3q]] 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=4M3Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4M3Q 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]] 2.718&#8491;</td></tr>
 +
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=24K:TRANS-4-{[2-(BUTYLAMINO)-5-(PYRIDIN-2-YL)PYRIMIDIN-4-YL]AMINO}CYCLOHEXANOL'>24K</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=4m3q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m3q OCA], [https://pdbe.org/4m3q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4m3q RCSB], [https://www.ebi.ac.uk/pdbsum/4m3q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4m3q 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>
 +
<div style="background-color:#fffaf0;">
 +
== Publication Abstract from PubMed ==
 +
Abnormal activation or overexpression of Mer receptor tyrosine kinase has been implicated in survival signaling and chemoresistance in many human cancers. Consequently, Mer is a promising novel cancer therapeutic target. A structure-based drug design approach using a pseudo-ring replacement strategy was developed and validated to discover a new family of pyridinepyrimidine analogues as potent Mer inhibitors. Through SAR studies, 10 (UNC2250) was identified as the lead compound for further investigation based on high selectivity against other kinases and good pharmacokinetic properties. When applied to live cells, 10 inhibited steady-state phosphorylation of endogenous Mer with an IC50 of 9.8 nM and blocked ligand-stimulated activation of a chimeric EGFR-Mer protein. Treatment with 10 also resulted in decreased colony-forming potential in rhabdoid and NSCLC tumor cells, thereby demonstrating functional antitumor activity. The results provide a rationale for further investigation of this compound for therapeutic application in patients with cancer.
-
==Function==
+
Pseudo-Cyclization through Intramolecular Hydrogen Bond Enables Discovery of Pyridine Substituted Pyrimidines as New Mer Kinase Inhibitors.,Zhang W, Zhang D, Stashko MA, Deryckere D, Hunter D, Kireev D, Miley MJ, Cummings C, Lee M, Norris-Drouin J, Stewart WM, Sather S, Zhou Y, Kirkpatrick G, Machius M, Janzen WP, Earp HS, Graham DK, Frye SV, Wang X J Med Chem. 2013 Nov 20. PMID:24195762<ref>PMID:24195762</ref>
-
[[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>
+
-
==About this Structure==
+
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-
[[4m3q]] 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=4M3Q OCA].
+
</div>
 +
<div class="pdbe-citations 4m3q" style="background-color:#fffaf0;"></div>
-
==Reference==
+
==See Also==
-
<ref group="xtra">PMID:024195762</ref><references group="xtra"/><references/>
+
*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
-
[[Category: Human]]
+
== References ==
-
[[Category: Receptor protein-tyrosine kinase]]
+
<references/>
-
[[Category: Cummings, C.]]
+
__TOC__
-
[[Category: DeRyckere, D.]]
+
</StructureSection>
-
[[Category: Earp, H S.]]
+
[[Category: Homo sapiens]]
-
[[Category: Frye, S.]]
+
[[Category: Large Structures]]
-
[[Category: Graham, D K.]]
+
[[Category: Cummings C]]
-
[[Category: Hunter, D.]]
+
[[Category: DeRyckere D]]
-
[[Category: Janzen, W P.]]
+
[[Category: Earp HS]]
-
[[Category: Kireev, D B.]]
+
[[Category: Frye S]]
-
[[Category: Kirkpatrick, G.]]
+
[[Category: Graham DK]]
-
[[Category: Lee, M.]]
+
[[Category: Hunter D]]
-
[[Category: Machius, M.]]
+
[[Category: Janzen WP]]
-
[[Category: Miley, M.]]
+
[[Category: Kireev DB]]
-
[[Category: Norris-Drouin, J.]]
+
[[Category: Kirkpatrick G]]
-
[[Category: Sather, S.]]
+
[[Category: Lee M]]
-
[[Category: Stashko, M A.]]
+
[[Category: Machius M]]
-
[[Category: Stewart, W M.]]
+
[[Category: Miley M]]
-
[[Category: Wang, X.]]
+
[[Category: Norris-Drouin J]]
-
[[Category: Zhang, D.]]
+
[[Category: Sather S]]
-
[[Category: Zhang, W.]]
+
[[Category: Stashko MA]]
-
[[Category: Zhou, Y.]]
+
[[Category: Stewart WM]]
-
[[Category: Acute lymphoblastic leukemia]]
+
[[Category: Wang X]]
-
[[Category: Rational structure-based drug design]]
+
[[Category: Zhang D]]
-
[[Category: Transferase-transferase inhibitor complex]]
+
[[Category: Zhang W]]
-
[[Category: Tyrosine kinase]]
+
[[Category: Zhou Y]]

Current revision

Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC1917

PDB ID 4m3q

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4m3q"
Personal tools