View source for 6gjd


==Erk2 signalling protein==
<StructureSection load='6gjd' size='340' side='right'caption='[[6gjd]], [[Resolution|resolution]] 1.58&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6gjd]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GJD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6GJD FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.58&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=F0E:cyclooctyl+~{N}-[3-[[4-[5-[[(3~{R})-1-[2-oxidanylidene-2-[4-(4-pyrimidin-2-ylphenyl)piperazin-1-yl]ethyl]pyrrolidin-3-yl]carbonylamino]-1~{H}-indazol-3-yl]pyridin-2-yl]carbonylamino]propyl]carbamate'>F0E</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=6gjd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gjd OCA], [https://pdbe.org/6gjd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6gjd RCSB], [https://www.ebi.ac.uk/pdbsum/6gjd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6gjd ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/MK01_HUMAN MK01_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, 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.<ref>PMID:7588608</ref> <ref>PMID:8622688</ref> <ref>PMID:9480836</ref> <ref>PMID:9687510</ref> <ref>PMID:9649500</ref> <ref>PMID:9596579</ref> <ref>PMID:10637505</ref> <ref>PMID:10617468</ref> <ref>PMID:11154262</ref> <ref>PMID:12110590</ref> <ref>PMID:12356731</ref> <ref>PMID:12974390</ref> <ref>PMID:12794087</ref> <ref>PMID:12792650</ref> <ref>PMID:15184391</ref> <ref>PMID:15241487</ref> <ref>PMID:15952796</ref> <ref>PMID:15616583</ref> <ref>PMID:15788397</ref> <ref>PMID:15664191</ref> <ref>PMID:16581800</ref> <ref>PMID:19879846</ref> <ref>PMID:19265199</ref>   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.<ref>PMID:7588608</ref> <ref>PMID:8622688</ref> <ref>PMID:9480836</ref> <ref>PMID:9687510</ref> <ref>PMID:9649500</ref> <ref>PMID:9596579</ref> <ref>PMID:10637505</ref> <ref>PMID:10617468</ref> <ref>PMID:11154262</ref> <ref>PMID:12110590</ref> <ref>PMID:12356731</ref> <ref>PMID:12974390</ref> <ref>PMID:12794087</ref> <ref>PMID:12792650</ref> <ref>PMID:15184391</ref> <ref>PMID:15241487</ref> <ref>PMID:15952796</ref> <ref>PMID:15616583</ref> <ref>PMID:15788397</ref> <ref>PMID:15664191</ref> <ref>PMID:16581800</ref> <ref>PMID:19879846</ref> <ref>PMID:19265199</ref> 
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== Publication Abstract from PubMed ==
Target engagement is a key concept in drug discovery and its direct measurement can provide a quantitative understanding of drug efficacy and/or toxicity. Failure to demonstrate target occupancy in relevant cells and tissues has been recognised as a contributing factor to the low success rate of clinical drug development. Several techniques are emerging to quantify target engagement in cells; however, in situ measurements remain challenging, mainly due to technical limitations. Here, we report the development of a non-covalent clickable probe, based on SCH772984, a slow off-rate ERK1/2 inhibitor, which enabled efficient pull down of ERK1/2 protein via click reaction with tetrazine tagged agarose beads. This was used in a competition setting to measure relative target occupancy by selected ERK1/2 inhibitors. As a reference we used the cellular thermal shift assay, a label-free biophysical assay relying solely on ligand-induced thermodynamic stabilization of proteins. To validate the EC50 values measured by both methods, the results were compared with IC50 data for the phosphorylation of RSK, a downstream substrate of ERK1/2 used as a functional biomarker of ERK1/2 inhibition. We showed that a slow off-rate reversible probe can be used to efficiently pull down cellular proteins, significantly extending the potential of the approach beyond the need for covalent or photoaffinity warheads.

Quantitation of ERK1/2 inhibitor cellular target occupancies with a reversible slow off-rate probe.,Lebraud H, Surova O, Courtin A, O'Reilly M, Valenzano CR, Nordlund P, Heightman TD Chem Sci. 2018 Sep 17;9(45):8608-8618. doi: 10.1039/c8sc02754d. eCollection 2018 , Dec 7. PMID:30568786<ref>PMID:30568786</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
*[[Mitogen-activated protein kinase 3D structures|Mitogen-activated protein kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: O'Reilly M]]