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5hd7

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Revision as of 09:58, 22 November 2017

Dissecting Therapeutic Resistance to ERK Inhibition Rat Mutant SCH772984 in complex with (3R)-1-(2-oxo-2-{4-[4-(pyrimidin-2-yl)phenyl]piperazin-1-yl}ethyl)-N-[3-(pyridin-4-yl)-2H-indazol-5-yl]pyrrolidine-3-carboxamide

Structural highlights

5hd7 is a 1 chain structure with sequence from Buffalo rat. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	5hd4
Gene:	Mapk1, Erk2, Mapk, Prkm1 (Buffalo rat)
Activity:	Mitogen-activated protein kinase, with EC number 2.7.11.24
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[MK01_RAT] 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, DCC, 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. May play a role in the spindle assembly checkpoint.^[1] Acts as a transcriptional repressor. Binds to a [GC]AAA[GC] consensus sequence. Repress the expression of interferon gamma-induced genes. Seems to bind to the promoter of CCL5, DMP1, IFIH1, IFITM1, IRF7, IRF9, LAMP3, OAS1, OAS2, OAS3 and STAT1. Transcriptional activity is independent of kinase activity (By similarity).^[2]

Publication Abstract from PubMed

The MAPK pathway is frequently activated in many human cancers, particularly melanomas. A single nucleotide mutation in BRAF resulting in the substitution of glutamic acid for valine (V600E) causes constitutive activation of the downstream MAPK pathway. Selective BRAF and MEK inhibitor therapies have demonstrated remarkable anti-tumor responses in BRAFV600E mutant melanoma patients. However, initial tumor shrinkage is transient and the vast majority of patients develop resistance. We previously reported that SCH772984, an ERK 1/2 inhibitor, effectively suppressed MAPK pathway signaling and cell proliferation in BRAF, MEK and concurrent BRAF/MEK inhibitor resistant tumor models. ERK inhibitors are currently being evaluated in clinical trials and in anticipation of the likelihood of clinical resistance, we sought to prospectively model acquired resistance to SCH772984. Our data show that long term exposure of cells to SCH772984 leads to acquired resistance, attributable to a mutation of glycine to aspartic acid (G186D) in the DFG motif of ERK1. Structural and biophysical studies demonstrated specific defects in SCH772984 binding to mutant ERK. Taken together, these studies describe the interaction of SCH772984 with ERK and identify a novel mechanism of ERK inhibitor resistance through mutation of a single residue within the DFG motif.

Dissecting Therapeutic Resistance to ERK Inhibition.,Jha S, Morris EJ, Hruza A, Mansueto MS, Schroeder G, Arbanas J, McMasters D, Restaino CR, Dayananth P, Black S, Elsen NL, Mannarino A, Cooper A, Fawell S, Zawel L, Jayaraman L, Samatar AA Mol Cancer Ther. 2016 Feb 1. pii: molcanther.0172.2015. PMID:26832798^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ma W, Shang Y, Wei Z, Wen W, Wang W, Zhang M. Phosphorylation of DCC by ERK2 is facilitated by direct docking of the receptor P1 domain to the kinase. Structure. 2010 Nov 10;18(11):1502-11. PMID:21070949 doi:10.1016/j.str.2010.08.011
↑ Ma W, Shang Y, Wei Z, Wen W, Wang W, Zhang M. Phosphorylation of DCC by ERK2 is facilitated by direct docking of the receptor P1 domain to the kinase. Structure. 2010 Nov 10;18(11):1502-11. PMID:21070949 doi:10.1016/j.str.2010.08.011
↑ Jha S, Morris EJ, Hruza A, Mansueto MS, Schroeder G, Arbanas J, McMasters D, Restaino CR, Dayananth P, Black S, Elsen NL, Mannarino A, Cooper A, Fawell S, Zawel L, Jayaraman L, Samatar AA. Dissecting Therapeutic Resistance to ERK Inhibition. Mol Cancer Ther. 2016 Feb 1. pii: molcanther.0172.2015. PMID:26832798 doi:http://dx.doi.org/10.1158/1535-7163.MCT-15-0172

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5hd7"

@@ Line 3: / Line 3: @@
 <StructureSection load='5hd7' size='340' side='right' caption='[[5hd7]], [[Resolution|resolution]] 1.69&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5hd7]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HD7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HD7 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5hd7]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HD7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HD7 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=38Z:(3R)-1-(2-OXO-2-{4-[4-(PYRIMIDIN-2-YL)PHENYL]PIPERAZIN-1-YL}ETHYL)-N-[3-(PYRIDIN-4-YL)-2H-INDAZOL-5-YL]PYRROLIDINE-3-CARBOXAMIDE'>38Z</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">[[5hd4|5hd4]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Mapk1, Erk2, Mapk, Prkm1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</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=5hd7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hd7 OCA], [http://pdbe.org/5hd7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hd7 RCSB], [http://www.ebi.ac.uk/pdbsum/5hd7 PDBsum]</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=5hd7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hd7 OCA], [http://pdbe.org/5hd7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hd7 RCSB], [http://www.ebi.ac.uk/pdbsum/5hd7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5hd7 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Buffalo rat]]
 [[Category: Mitogen-activated protein kinase]]
 [[Category: Arbanas, J]]

5hd7

From Proteopedia

Revision as of 09:58, 22 November 2017

Dissecting Therapeutic Resistance to ERK Inhibition Rat Mutant SCH772984 in complex with (3R)-1-(2-oxo-2-{4-[4-(pyrimidin-2-yl)phenyl]piperazin-1-yl}ethyl)-N-[3-(pyridin-4-yl)-2H-indazol-5-yl]pyrrolidine-3-carboxamide

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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