4xv1
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4xv1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. The March 2016 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Raf Protein Kinases'' by David Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2016_3 10.2210/rcsb_pdb/mom_2016_3]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XV1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XV1 FirstGlance]. <br> | <table><tr><td colspan='2'>[[4xv1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. The March 2016 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Raf Protein Kinases'' by David Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2016_3 10.2210/rcsb_pdb/mom_2016_3]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XV1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XV1 FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=904:N-(3-{[5-(2-CYCLOPROPYLPYRIMIDIN-5-YL)-1H-PYRROLO[2,3-B]PYRIDIN-3-YL]CARBONYL}-2,4-DIFLUOROPHENYL)-N-ETHYL-N-METHYLSULFURIC+DIAMIDE'>904</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.47Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=904:N-(3-{[5-(2-CYCLOPROPYLPYRIMIDIN-5-YL)-1H-PYRROLO[2,3-B]PYRIDIN-3-YL]CARBONYL}-2,4-DIFLUOROPHENYL)-N-ETHYL-N-METHYLSULFURIC+DIAMIDE'>904</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=4xv1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xv1 OCA], [https://pdbe.org/4xv1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xv1 RCSB], [https://www.ebi.ac.uk/pdbsum/4xv1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xv1 ProSAT]</span></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=4xv1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xv1 OCA], [https://pdbe.org/4xv1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xv1 RCSB], [https://www.ebi.ac.uk/pdbsum/4xv1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xv1 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/BRAF_HUMAN BRAF_HUMAN] Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron. | [https://www.uniprot.org/uniprot/BRAF_HUMAN BRAF_HUMAN] Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron. | ||
| - | <div style="background-color:#fffaf0;"> | ||
| - | == Publication Abstract from PubMed == | ||
| - | Oncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling. Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma. However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers. Structurally diverse ATP-competitive RAF inhibitors can either inhibit or paradoxically activate the MAPK pathway, depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. Here we have identified next-generation RAF inhibitors (dubbed 'paradox breakers') that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In cells that express the same HRAS mutation prevalent in squamous tumours from patients treated with RAF inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro and in vivo growth and induced expression of MAPK pathway response genes; by contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox breakers also overcame several known mechanisms of resistance to first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from paradoxical activation might yield both improved safety and more durable efficacy than first-generation RAF inhibitors, a concept currently undergoing human clinical evaluation with PLX8394. | ||
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| - | RAF inhibitors that evade paradoxical MAPK pathway activation.,Zhang C, Spevak W, Zhang Y, Burton EA, Ma Y, Habets G, Zhang J, Lin J, Ewing T, Matusow B, Tsang G, Marimuthu A, Cho H, Wu G, Wang W, Fong D, Nguyen H, Shi S, Womack P, Nespi M, Shellooe R, Carias H, Powell B, Light E, Sanftner L, Walters J, Tsai J, West BL, Visor G, Rezaei H, Lin PS, Nolop K, Ibrahim PN, Hirth P, Bollag G Nature. 2015 Oct 22;526(7574):583-6. doi: 10.1038/nature14982. Epub 2015 Oct 14. PMID:26466569<ref>PMID:26466569</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 4xv1" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
Current revision
B-Raf Kinase V600E oncogenic mutant in complex with PLX7904
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