4dli: Difference between revisions
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[[ | ==Human p38 MAP kinase in complex with RL87== | ||
<StructureSection load='4dli' size='340' side='right' caption='[[4dli]], [[Resolution|resolution]] 1.91Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4dli]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DLI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DLI FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=IRG:N~4~-CYCLOPROPYL-2-PHENYLQUINAZOLINE-4,7-DIAMINE'>IRG</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4dlj|4dlj]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAPK14, CSBP, CSBP1, CSBP2, CSPB1, MXI2, SAPK2A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </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=4dli FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dli OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dli RCSB], [http://www.ebi.ac.uk/pdbsum/4dli PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The vast majority of small molecules known to modulate kinase activity, target the highly conserved ATP-pocket. Consequently, such ligands are often less specific and in case of inhibitors, this leads to the inhibition of multiple kinases. Thus, selective modulation of kinase function remains a major hurdle. One of the next great challenges in kinase research is the identification of ligands which bind to less conserved sites and target the non-catalytic functions of protein kinases. However, approaches that allow for the unambiguous identification of molecules that bind to these less conserved sites are few in number. We have previously reported the use of fluorescent labels in kinases (FLiK) to develop direct kinase binding assays that exclusively detect ligands which stabilize inactive (DFG-out) kinase conformations. Here, we present the successful application of the FLiK approach to develop a high-throughput binding assay capable of directly monitoring ligand binding to a remote site within the MAPK insert of p38alpha mitogen-activated protein kinase (MAPK). Guided by the crystal structure of an initially identified hit molecule in complex with p38alpha, we developed a tight binding ligand which may serve as an ideal starting point for further investigations of the biological function of the MAPK insert in regulating the p38alpha signaling pathway. | |||
Fluorophore labeled kinase detects ligands that bind within the MAPK insert of p38alpha kinase.,Getlik M, Simard JR, Termathe M, Grutter C, Rabiller M, van Otterlo WA, Rauh D PLoS One. 2012;7(7):e39713. Epub 2012 Jul 2. PMID:22768308<ref>PMID:22768308</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | |||
*[[Mitogen-activated protein kinase|Mitogen-activated protein kinase]] | |||
== | == References == | ||
[[ | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Mitogen-activated protein kinase]] | [[Category: Mitogen-activated protein kinase]] | ||
[[Category: Getlik, M | [[Category: Getlik, M]] | ||
[[Category: Gruetter, C | [[Category: Gruetter, C]] | ||
[[Category: Rauh, D | [[Category: Rauh, D]] | ||
[[Category: Simard, J R | [[Category: Simard, J R]] | ||
[[Category: Lipid binding pocket]] | [[Category: Lipid binding pocket]] | ||
[[Category: Map kinase insert]] | [[Category: Map kinase insert]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
[[Category: Transferase-transferase inhibitor complex]] | [[Category: Transferase-transferase inhibitor complex]] | ||
Revision as of 19:17, 9 December 2014
Human p38 MAP kinase in complex with RL87Human p38 MAP kinase in complex with RL87
Structural highlights
Publication Abstract from PubMedThe vast majority of small molecules known to modulate kinase activity, target the highly conserved ATP-pocket. Consequently, such ligands are often less specific and in case of inhibitors, this leads to the inhibition of multiple kinases. Thus, selective modulation of kinase function remains a major hurdle. One of the next great challenges in kinase research is the identification of ligands which bind to less conserved sites and target the non-catalytic functions of protein kinases. However, approaches that allow for the unambiguous identification of molecules that bind to these less conserved sites are few in number. We have previously reported the use of fluorescent labels in kinases (FLiK) to develop direct kinase binding assays that exclusively detect ligands which stabilize inactive (DFG-out) kinase conformations. Here, we present the successful application of the FLiK approach to develop a high-throughput binding assay capable of directly monitoring ligand binding to a remote site within the MAPK insert of p38alpha mitogen-activated protein kinase (MAPK). Guided by the crystal structure of an initially identified hit molecule in complex with p38alpha, we developed a tight binding ligand which may serve as an ideal starting point for further investigations of the biological function of the MAPK insert in regulating the p38alpha signaling pathway. Fluorophore labeled kinase detects ligands that bind within the MAPK insert of p38alpha kinase.,Getlik M, Simard JR, Termathe M, Grutter C, Rabiller M, van Otterlo WA, Rauh D PLoS One. 2012;7(7):e39713. Epub 2012 Jul 2. PMID:22768308[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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