6ges: Difference between revisions
New page: '''Unreleased structure''' The entry 6ges is ON HOLD Authors: Chaikuad, A., Suman, R., Gray, N.S., Knapp, S., Structural Genomics Consortium (SGC) Description: Crystal structure of ERK... |
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The | ==Crystal structure of ERK1 covalently bound to SM1-71== | ||
<StructureSection load='6ges' size='340' side='right'caption='[[6ges]], [[Resolution|resolution]] 2.07Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6ges]] 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=6GES OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GES FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6H3:N-{2-[(5-CHLORO-2-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIMIDIN-4-YL)AMINO]PHENYL}PROPANAMIDE'>6H3</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=EWH:~{N}-[2-[[5-chloranyl-2-[[4-(4-methylpiperazin-1-yl)phenyl]amino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide'>EWH</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6g54|6g54]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAPK3, ERK1, PRKM3 ([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/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=6ges FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ges OCA], [http://pdbe.org/6ges PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ges RCSB], [http://www.ebi.ac.uk/pdbsum/6ges PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ges ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/MK03_HUMAN MK03_HUMAN]] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade.<ref>PMID:8325880</ref> <ref>PMID:9155018</ref> <ref>PMID:9480836</ref> <ref>PMID:10393181</ref> <ref>PMID:10617468</ref> <ref>PMID:12356731</ref> <ref>PMID:15952796</ref> <ref>PMID:12110590</ref> <ref>PMID:12974390</ref> <ref>PMID:15788397</ref> <ref>PMID:16581800</ref> <ref>PMID:19265199</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Covalent kinase inhibitors, which typically target cysteine residues, represent an important class of clinically relevant compounds. Approximately 215 kinases are known to have potentially targetable cysteines distributed across 18 spatially distinct locations proximal to the ATP-binding pocket. However, only 40 kinases have been covalently targeted, with certain cysteine sites being the primary focus. To address this disparity, we have developed a strategy that combines the use of a multi-targeted acrylamide-modified inhibitor, SM1-71, with a suite of complementary chemoproteomic and cellular approaches to identify additional targetable cysteines. Using this single multi-targeted compound, we successfully identified 23 kinases that are amenable to covalent inhibition including MKNK2, MAP2K1/2/3/4/6/7, GAK, AAK1, BMP2K, MAP3K7, MAPKAPK5, GSK3A/B, MAPK1/3, SRC, YES1, FGFR1, ZAK (MLTK), MAP3K1, LIMK1, and RSK2. The identification of nine of these kinases previously not targeted by a covalent inhibitor increases the number of targetable kinases and highlights opportunities for covalent kinase inhibitor development. | |||
Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome.,Rao S, Gurbani D, Du G, Everley RA, Browne CM, Chaikuad A, Li T, Schroder M, Gondi S, Ficarro SB, Sim T, Kim ND, Berberich MJ, Knapp S, Marto JA, Westover KD, Sorger PK, Gray NS Cell Chem Biol. 2019 Mar 18. pii: S2451-9456(19)30076-5. doi:, 10.1016/j.chembiol.2019.02.021. PMID:30982749<ref>PMID:30982749</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6ges" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Mitogen-activated protein kinase]] | |||
[[Category: Arrowsmith, C H]] | |||
[[Category: Bountra, C]] | |||
[[Category: Chaikuad, A]] | [[Category: Chaikuad, A]] | ||
[[Category: Gray, N | [[Category: Edwards, A M]] | ||
[[Category: Gray, N S]] | |||
[[Category: Knapp, S]] | [[Category: Knapp, S]] | ||
[[Category: Structural genomic]] | |||
[[Category: Suman, R]] | [[Category: Suman, R]] | ||
[[Category: | [[Category: Covalent inhibitor]] | ||
[[Category: Kinase]] | |||
[[Category: Mapk]] | |||
[[Category: Sgc]] | |||
[[Category: Transferase]] | |||
Latest revision as of 12:11, 1 May 2019
Crystal structure of ERK1 covalently bound to SM1-71Crystal structure of ERK1 covalently bound to SM1-71
Structural highlights
Function[MK03_HUMAN] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] Publication Abstract from PubMedCovalent kinase inhibitors, which typically target cysteine residues, represent an important class of clinically relevant compounds. Approximately 215 kinases are known to have potentially targetable cysteines distributed across 18 spatially distinct locations proximal to the ATP-binding pocket. However, only 40 kinases have been covalently targeted, with certain cysteine sites being the primary focus. To address this disparity, we have developed a strategy that combines the use of a multi-targeted acrylamide-modified inhibitor, SM1-71, with a suite of complementary chemoproteomic and cellular approaches to identify additional targetable cysteines. Using this single multi-targeted compound, we successfully identified 23 kinases that are amenable to covalent inhibition including MKNK2, MAP2K1/2/3/4/6/7, GAK, AAK1, BMP2K, MAP3K7, MAPKAPK5, GSK3A/B, MAPK1/3, SRC, YES1, FGFR1, ZAK (MLTK), MAP3K1, LIMK1, and RSK2. The identification of nine of these kinases previously not targeted by a covalent inhibitor increases the number of targetable kinases and highlights opportunities for covalent kinase inhibitor development. Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome.,Rao S, Gurbani D, Du G, Everley RA, Browne CM, Chaikuad A, Li T, Schroder M, Gondi S, Ficarro SB, Sim T, Kim ND, Berberich MJ, Knapp S, Marto JA, Westover KD, Sorger PK, Gray NS Cell Chem Biol. 2019 Mar 18. pii: S2451-9456(19)30076-5. doi:, 10.1016/j.chembiol.2019.02.021. PMID:30982749[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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