4w8d
From Proteopedia
(Difference between revisions)
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| - | ''' | + | ==Crystal structure of MST3 with a pyrrolopyrimidine inhibitor (PF-06454589).== |
| + | <StructureSection load='4w8d' size='340' side='right' caption='[[4w8d]], [[Resolution|resolution]] 1.77Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4w8d]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4W8D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4W8D FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3JA:5-(1-METHYL-1H-PYRAZOL-4-YL)-4-(MORPHOLIN-4-YL)-7H-PYRROLO[2,3-D]PYRIMIDINE'>3JA</scene></td></tr> | ||
| + | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4w8e|4w8e]]</td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=4w8d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4w8d OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4w8d RCSB], [http://www.ebi.ac.uk/pdbsum/4w8d PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/STK24_HUMAN STK24_HUMAN]] Serine/threonine-protein kinase that acts on both serine and threonine residues and promotes apoptosis in response to stress stimuli and caspase activation. Mediates oxidative-stress-induced cell death by modulating phosphorylation of JNK1-JNK2 (MAPK8 and MAPK9), p38 (MAPK11, MAPK12, MAPK13 and MAPK14) during oxidative stress. Plays a role in a staurosporine-induced caspase-independent apoptotic pathway by regulating the nuclear translocation of AIFM1 and ENDOG and the DNase activity associated with ENDOG. Phosphorylates STK38L on 'Thr-442' and stimulates its kinase activity. Regulates cellular migration with alteration of PTPN12 activity and PXN phosphorylation: phosphorylates PTPN12 and inhibits its activity and may regulate PXN phosphorylation through PTPN12. May act as a key regulator of axon regeneration in the optic nerve and radial nerve.<ref>PMID:16314523</ref> <ref>PMID:17046825</ref> <ref>PMID:19604147</ref> <ref>PMID:19855390</ref> <ref>PMID:19782762</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the discovery and optimization of a novel series of potent LRRK2 inhibitors, focusing on improving kinome selectivity using a surrogate crystallography approach. This resulted in the identification of 14 (PF-06447475), a highly potent, brain penetrant and selective LRRK2 inhibitor which has been further profiled in in vivo safety and pharmacodynamic studies. | ||
| - | + | Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor.,Henderson JL, Kormos BL, Hayward MM, Coffman KJ, Jasti J, Kurumbail RG, Wager TT, Verhoest PR, Noell GS, Chen Y, Needle E, Berger Z, Steyn SJ, Houle C, Hirst WD, Galatsis P J Med Chem. 2015 Jan 8;58(1):419-32. doi: 10.1021/jm5014055. Epub 2014 Nov 17. PMID:25353650<ref>PMID:25353650</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| - | [[Category: | + | <references/> |
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Non-specific serine/threonine protein kinase]] | ||
| + | [[Category: Griffor, M]] | ||
[[Category: Jasti, J]] | [[Category: Jasti, J]] | ||
| - | [[Category: Kurumbail, R | + | [[Category: Kurumbail, R G]] |
| - | + | ||
[[Category: Song, X]] | [[Category: Song, X]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Kinase]] | ||
| + | [[Category: Mst3]] | ||
| + | [[Category: Pyrrolopyrimidine]] | ||
| + | [[Category: Transferase-transferase inhibitor complex]] | ||
Revision as of 12:00, 18 March 2015
Crystal structure of MST3 with a pyrrolopyrimidine inhibitor (PF-06454589).
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