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==MerTK kinase domain in complex with quinazoline-based inhbitor== | ==MerTK kinase domain in complex with quinazoline-based inhbitor== | ||
<StructureSection load='7avy' size='340' side='right'caption='[[7avy]]' scene=''> | <StructureSection load='7avy' size='340' side='right'caption='[[7avy]], [[Resolution|resolution]] 2.31Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AVY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AVY FirstGlance]. <br> | <table><tr><td colspan='2'>[[7avy]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AVY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AVY FirstGlance]. <br> | ||
</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=7avy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7avy OCA], [https://pdbe.org/7avy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7avy RCSB], [https://www.ebi.ac.uk/pdbsum/7avy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7avy ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=S4E:N-(2-(2-cyclopropylethoxy)pyrimidin-5-yl)-7-methoxy-6-(piperidin-4-ylmethoxy)quinazolin-4-amine'>S4E</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MERTK, MER ([https://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'>[https://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [https://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=7avy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7avy OCA], [https://pdbe.org/7avy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7avy RCSB], [https://www.ebi.ac.uk/pdbsum/7avy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7avy ProSAT]</span></td></tr> | |||
</table> | </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 == | |||
Mer is a member of the TAM (Tyro3, Axl, Mer) kinase family that has been associated with cancer progression, metastasis, and drug resistance. Their essential function in immune homeostasis has prompted an interest in their role as modulators of antitumor immune response in the tumor microenvironment. Here we illustrate the outcomes of an extensive lead-generation campaign for identification of Mer inhibitors, focusing on the results from concurrent, orthogonal high-throughput screening approaches. Data mining, HT (high-throughput), and DECL (DNA-encoded chemical library) screens offered means to evaluate large numbers of compounds. We discuss campaign strategy and screening outcomes, and exemplify series resulting from prioritization of hits that were identified. Concurrent execution of HT and DECL screening successfully yielded a large number of potent, selective, and novel starting points, covering a range of selectivity profiles across the TAM family members and modes of kinase binding, and offered excellent start points for lead development. | |||
Generating Selective Leads for Mer Kinase Inhibitors-Example of a Comprehensive Lead-Generation Strategy.,Nissink JWM, Bazzaz S, Blackett C, Clark MA, Collingwood O, Disch JS, Gikunju D, Goldberg K, Guilinger JP, Hardaker E, Hennessy EJ, Jetson R, Keefe AD, McCoull W, McMurray L, Olszewski A, Overman R, Pflug A, Preston M, Rawlins PB, Rivers E, Schimpl M, Smith P, Truman C, Underwood E, Warwicker J, Winter-Holt J, Woodcock S, Zhang Y J Med Chem. 2021 Mar 8. doi: 10.1021/acs.jmedchem.0c01904. PMID:33683117<ref>PMID:33683117</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7avy" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Blackett C]] | [[Category: Receptor protein-tyrosine kinase]] | ||
[[Category: Collingwood O]] | [[Category: Blackett, C]] | ||
[[Category: Goldberg K]] | [[Category: Collingwood, O]] | ||
[[Category: Hardaker E]] | [[Category: Goldberg, K]] | ||
[[Category: Hennessy | [[Category: Hardaker, E]] | ||
[[Category: McCoull W]] | [[Category: Hennessy, E J]] | ||
[[Category: McMurray L]] | [[Category: McCoull, W]] | ||
[[Category: Nissink | [[Category: McMurray, L]] | ||
[[Category: Overman R]] | [[Category: Nissink, J W.M]] | ||
[[Category: Pflug A]] | [[Category: Overman, R]] | ||
[[Category: Preston M]] | [[Category: Pflug, A]] | ||
[[Category: Rawlins P]] | [[Category: Preston, M]] | ||
[[Category: Rivers E]] | [[Category: Rawlins, P]] | ||
[[Category: Schimpl M]] | [[Category: Rivers, E]] | ||
[[Category: Smith P]] | [[Category: Schimpl, M]] | ||
[[Category: Truman C]] | [[Category: Smith, P]] | ||
[[Category: Underwood E]] | [[Category: Truman, C]] | ||
[[Category: Warwicker J]] | [[Category: Underwood, E]] | ||
[[Category: Winter J]] | [[Category: Warwicker, J]] | ||
[[Category: Woodcock S]] | [[Category: Winter, J]] | ||
[[Category: Woodcock, S]] | |||
[[Category: Inhibitor]] | |||
[[Category: Oncology]] | |||
[[Category: Signaling protein]] | |||
[[Category: Structure-based drug design]] | |||
[[Category: Type1 5 kinase inhibitor]] | |||
[[Category: Tyrosine kinase]] | |||