3c4c: Difference between revisions

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-[[Image:3c4c.jpg|left|200px]]
- {{Structure
+==B-Raf Kinase in Complex with PLX4720==
-|PDB= 3c4c |SIZE=350|CAPTION= <scene name='initialview01'>3c4c</scene>, resolution 2.57&Aring;
+<StructureSection load='3c4c' size='340' side='right'caption='[[3c4c]], [[Resolution|resolution]] 2.57&Aring;' scene=''>
-|SITE= <scene name='pdbsite=AC1:324+Binding+Site+For+Residue+A+2'>AC1</scene> and <scene name='pdbsite=AC2:324+Binding+Site+For+Residue+B+3'>AC2</scene>
+== Structural highlights ==
-|LIGAND= <scene name='pdbligand=324:'>324</scene>
+<table><tr><td colspan='2'>[[3c4c]] is a 2 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=3C4C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3C4C FirstGlance]. <br>
-|ACTIVITY= [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1]
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.57&#8491;</td></tr>
-|GENE= BRAF, BRAF1, RAFB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=324:N-{3-[(5-CHLORO-1H-PYRROLO[2,3-B]PYRIDIN-3-YL)CARBONYL]-2,4-DIFLUOROPHENYL}PROPANE-1-SULFONAMIDE'>324</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=3c4c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3c4c OCA], [https://pdbe.org/3c4c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3c4c RCSB], [https://www.ebi.ac.uk/pdbsum/3c4c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3c4c ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/BRAF_HUMAN BRAF_HUMAN] Note=Defects in BRAF are found in a wide range of cancers.<ref>PMID:18974108</ref>   Defects in BRAF may be a cause of colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500].<ref>PMID:18974108</ref>   Defects in BRAF are involved in lung cancer (LNCR) [MIM:[https://omim.org/entry/211980 211980]. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis.<ref>PMID:18974108</ref> <ref>PMID:12460919</ref>   Defects in BRAF are involved in non-Hodgkin lymphoma (NHL) [MIM:[https://omim.org/entry/605027 605027]. NHL is a cancer that starts in cells of the lymph system, which is part of the body's immune system. NHLs can occur at any age and are often marked by enlarged lymph nodes, fever and weight loss.<ref>PMID:18974108</ref> <ref>PMID:14612909</ref>   Defects in BRAF are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:[https://omim.org/entry/115150 115150]; also known as cardio-facio-cutaneous syndrome. CFC syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant.<ref>PMID:18974108</ref>   Defects in BRAF are the cause of Noonan syndrome type 7 (NS7) [MIM:[https://omim.org/entry/613706 613706]. Noonan syndrome is a disorder characterized by facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears. Other features can include short stature, a short neck with webbing or redundancy of skin, cardiac anomalies, deafness, motor delay and variable intellectual deficits.<ref>PMID:18974108</ref> <ref>PMID:19206169</ref>   Defects in BRAF are the cause of LEOPARD syndrome type 3 (LEOPARD3) [MIM:[https://omim.org/entry/613707 613707]. LEOPARD3 is a disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness.<ref>PMID:18974108</ref> <ref>PMID:19206169</ref>   Note=A chromosomal aberration involving BRAF is found in pilocytic astrocytomas. A tandem duplication of 2 Mb at 7q34 leads to the expression of a KIAA1549-BRAF fusion protein with a constitutive kinase activity and inducing cell transformation.<ref>PMID:18974108</ref>
+== 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.
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/c4/3c4c_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3c4c ConSurf].
+<div style="clear:both"></div>
-'''B-Raf Kinase in Complex with PLX4720'''
+==See Also==
+*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
+== References ==
-==Overview==
+<references/>
-BRAF(V600E) is the most frequent oncogenic protein kinase mutation known. Furthermore, inhibitors targeting "active" protein kinases have demonstrated significant utility in the therapeutic repertoire against cancer. Therefore, we pursued the development of specific kinase inhibitors targeting B-Raf, and the V600E allele in particular. By using a structure-guided discovery approach, a potent and selective inhibitor of active B-Raf has been discovered. PLX4720, a 7-azaindole derivative that inhibits B-Raf(V600E) with an IC(50) of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4720 preferentially inhibits the active B-Raf(V600E) kinase compared with a broad spectrum of other kinases, and potent cytotoxic effects are also exclusive to cells bearing the V600E allele. Consistent with the high degree of selectivity, ERK phosphorylation is potently inhibited by PLX4720 in B-Raf(V600E)-bearing tumor cell lines but not in cells lacking oncogenic B-Raf. In melanoma models, PLX4720 induces cell cycle arrest and apoptosis exclusively in B-Raf(V600E)-positive cells. In B-Raf(V600E)-dependent tumor xenograft models, orally dosed PLX4720 causes significant tumor growth delays, including tumor regressions, without evidence of toxicity. The work described here represents the entire discovery process, from initial identification through structural and biological studies in animal models to a promising therapeutic for testing in cancer patients bearing B-Raf(V600E)-driven tumors.
+__TOC__
+</StructureSection>
-==About this Structure==
-C4C is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3C4C OCA].
-==Reference==
-Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity., Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, Sproesser K, Li L, Smalley KS, Fong D, Zhu YL, Marimuthu A, Nguyen H, Lam B, Liu J, Cheung I, Rice J, Suzuki Y, Luu C, Settachatgul C, Shellooe R, Cantwell J, Kim SH, Schlessinger J, Zhang KY, West BL, Powell B, Habets G, Zhang C, Ibrahim PN, Hirth P, Artis DR, Herlyn M, Bollag G, Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3041-6. Epub 2008 Feb 19. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18287029 18287029]
 [[Category: Homo sapiens]]
-[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Large Structures]]
-[[Category: Single protein]]
+[[Category: Wang W]]
-[[Category: Wang, W.]]
+[[Category: Zhang KYJ]]
-[[Category: Zhang, K Y.J.]]
-[[Category: 324]]
-[[Category: atp-binding]]
-[[Category: b-raf]]
-[[Category: braf]]
-[[Category: cardiomyopathy]]
-[[Category: cytoplasm]]
-[[Category: disease mutation]]
-[[Category: metal-binding]]
-[[Category: nucleotide-binding]]
-[[Category: phorbol-ester binding]]
-[[Category: phosphoprotein]]
-[[Category: polymorphism]]
-[[Category: proto-oncogene]]
-[[Category: raf]]
-[[Category: serine/threonine kinase]]
-[[Category: serine/threonine-protein kinase]]
-[[Category: transferase]]
-[[Category: zinc]]
-[[Category: zinc-finger]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 19:02:30 2008''