View source for 4zxt


==Complex of ERK2 with catechol==
<StructureSection load='4zxt' size='340' side='right'caption='[[4zxt]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4zxt]] 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=4ZXT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZXT 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]] 2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CAQ:CATECHOL'>CAQ</scene>, <scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=NH4:AMMONIUM+ION'>NH4</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=4zxt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zxt OCA], [https://pdbe.org/4zxt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zxt RCSB], [https://www.ebi.ac.uk/pdbsum/4zxt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zxt 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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Various carcinogens induce EGFR/RAS/MAPK signaling, which is critical in the development of lung cancer. In particular, constitutive activation of extracellular signal-regulated kinase 2 (ERK2) is observed in many lung cancer patients, and therefore developing compounds capable of targeting ERK2 in lung carcinogenesis could be beneficial. We examined the therapeutic effect of catechol in lung cancer treatment. Catechol suppressed anchorage-independent growth of murine KP2 and human H460 lung cancer cell lines in a dose-dependent manner. Catechol inhibited ERK2 kinase activity in vitro, and its direct binding to the ERK2 active site was confirmed by X-ray crystallography. Phosphorylation of c-Myc, a substrate of ERK2, was decreased in catechol-treated lung cancer cells and resulted in reduced protein stability and subsequent down-regulation of total c-Myc. Treatment with catechol induced G1 phase arrest in lung cancer cells and decreased protein expression related to G1-S progression. In addition, we showed that catechol inhibited the growth of both allograft and xenograft lung cancer tumors in vivo. In summary, catechol exerted inhibitory effects on the ERK2/c-Myc signaling axis to reduce lung cancer tumor growth in vitro and in vivo, including a preclinical patient-derived xenograft (PDX) model. These findings suggest that catechol, a natural small molecule, possesses potential as a novel therapeutic agent against lung carcinogenesis in future clinical approaches.

A natural small molecule, catechol, induces c-Myc degradation by directly targeting ERK2 in lung cancer.,Lim DY, Shin SH, Lee MH, Malakhova M, Kurinov I, Wu Q, Xu J, Jiang Y, Dong Z, Liu K, Lee KY, Bae KB, Choi BY, Deng Y, Bode A, Dong Z Oncotarget. 2016 May 7. doi: 10.18632/oncotarget.9223. PMID:27167001<ref>PMID:27167001</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 4zxt" style="background-color:#fffaf0;"></div>

==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: Kurinov I]]
[[Category: Malakhova M]]