1rjb

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(New page: 200px<br /> <applet load="1rjb" size="450" color="white" frame="true" align="right" spinBox="true" caption="1rjb, resolution 2.10&Aring;" /> '''Crystal Structure o...)
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[[Image:1rjb.gif|left|200px]]<br />
 
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<applet load="1rjb" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1rjb, resolution 2.10&Aring;" />
 
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'''Crystal Structure of FLT3'''<br />
 
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==Overview==
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==Crystal Structure of FLT3==
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FLT3 is a type III receptor tyrosine kinase that is thought to play a key, role in hematopoiesis. Certain classes of FLT3 mutations cause, constitutively activated forms of the receptor that are found in, significant numbers of patients with acute myelogenous leukemia (AML). The, mutations occur either in the activation loop, for example, as point, mutations of Asp835 or as internal tandem duplication (ITD) sequences in, the juxtamembrane (JM) domain. To further understand the nature of FLT3, autoinhibition and regulation, we have determined the crystal structure of, the autoinhibited form of FLT3. This structure shows the autoinhibitory, conformation of a complete JM domain in this class of receptor tyrosine, kinases. The detailed inhibitory mechanism of the JM domain is revealed, which is likely utilized by other members of type III receptor tyrosine, kinases.
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<StructureSection load='1rjb' size='340' side='right'caption='[[1rjb]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1rjb]] 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=1RJB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1RJB FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1rjb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1rjb OCA], [https://pdbe.org/1rjb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1rjb RCSB], [https://www.ebi.ac.uk/pdbsum/1rjb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1rjb ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/FLT3_HUMAN FLT3_HUMAN] Defects in FLT3 are a cause of acute myelogenous leukemia (AML) [MIM:[https://omim.org/entry/601626 601626]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Note=Somatic mutations that lead to constitutive activation of FLT3 are frequent in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the activation loop of the kinase domain can result in a constitutively activated kinase.<ref>PMID:11090077</ref> <ref>PMID:16266983</ref> <ref>PMID:14504097</ref> <ref>PMID:9737679</ref> <ref>PMID:18305215</ref> <ref>PMID:11290608</ref> <ref>PMID:8946930</ref> <ref>PMID:11442493</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/FLT3_HUMAN FLT3_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways.<ref>PMID:7507245</ref> <ref>PMID:10080542</ref> <ref>PMID:11090077</ref> <ref>PMID:16266983</ref> <ref>PMID:16627759</ref> <ref>PMID:18490735</ref> <ref>PMID:20111072</ref> <ref>PMID:21067588</ref> <ref>PMID:21262971</ref> <ref>PMID:21516120</ref> <ref>PMID:14504097</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/rj/1rjb_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=1rjb ConSurf].
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<div style="clear:both"></div>
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==Disease==
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==See Also==
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Known diseases associated with this structure: Leukemia, acute lymphoblastic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=136351 136351]], Leukemia, acute myeloid OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=136351 136351]], Leukemia, acute myeloid, reduced survival in OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=136351 136351]], Melanoma, malignant sporadic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602216 602216]], Pancreatic cancer, sporadic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602216 602216]], Peutz-Jeghers syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602216 602216]], Testicular tumor, sporadic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602216 602216]]
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*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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1RJB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1RJB OCA].
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__TOC__
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</StructureSection>
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==Reference==
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The structural basis for autoinhibition of FLT3 by the juxtamembrane domain., Griffith J, Black J, Faerman C, Swenson L, Wynn M, Lu F, Lippke J, Saxena K, Mol Cell. 2004 Jan 30;13(2):169-78. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=14759363 14759363]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Transferase]]
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[[Category: Black J]]
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[[Category: Black, J.]]
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[[Category: Faerman C]]
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[[Category: Faerman, C.]]
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[[Category: Griffith J]]
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[[Category: Griffith, J.]]
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[[Category: Lippke J]]
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[[Category: Lippke, J.]]
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[[Category: Lu F]]
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[[Category: Lu, F.]]
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[[Category: Saxena K]]
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[[Category: Saxena, K.]]
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[[Category: Swenson L]]
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[[Category: Swenson, L.]]
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[[Category: Wynn M]]
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[[Category: Wynn, M.]]
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[[Category: autoinhibition]]
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[[Category: juxtamembrane domain]]
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[[Category: kinase]]
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[[Category: structure]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 19:04:28 2007''
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Current revision

Crystal Structure of FLT3

PDB ID 1rjb

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