1txd

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[[Image:1txd.jpg|left|200px]]<br /><applet load="1txd" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1txd, resolution 2.13&Aring;" />
 
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'''Crystal Structure of the DH/PH domains of Leukemia-associated RhoGEF'''<br />
 
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==Overview==
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==Crystal Structure of the DH/PH domains of Leukemia-associated RhoGEF==
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Rho guanine-nucleotide exchange factors (RhoGEFs) activate Rho GTPases, and thereby regulate cytoskeletal structure, gene transcription, and cell, migration. Leukemia-associated RhoGEF (LARG) belongs to a small subfamily, of RhoGEFs that are RhoA-selective and directly activated by the, Galpha12/13 family of heterotrimeric G proteins. Herein we describe the, atomic structures of the catalytic Dbl homology (DH) and pleckstrin, homology (PH) domains of LARG alone and in complex with RhoA. These, structures demonstrate that the DH/PH domains of LARG can undergo a, dramatic conformational change upon binding RhoA, wherein both the DH and, PH domains directly engage RhoA. Through mutational analysis we show that, full nucleotide exchange activity requires a novel N-terminal extension on, the DH domain that is predicted to exist in a broader family of RhoGEFs, that includes p115-RhoGEF, Lbc, Lfc, Net1, and Xpln, and identify regions, within the LARG PH domain that contribute to its ability to facilitate, nucleotide exchange in vitro. In crystals of the DH/PH-RhoA complex, the, active site of RhoA adopts two distinct GDP-excluding conformations among, the four unique complexes in the asymmetric unit. Similar changes were, previously observed in structures of nucleotide-free Ras and Ef-Tu. A, potential protein-docking site on the LARG PH domain is also evident and, appears to be conserved throughout the Lbc subfamily of RhoGEFs.
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<StructureSection load='1txd' size='340' side='right'caption='[[1txd]], [[Resolution|resolution]] 2.13&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1txd]] 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=1TXD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1TXD 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]] 2.13&#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=1txd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1txd OCA], [https://pdbe.org/1txd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1txd RCSB], [https://www.ebi.ac.uk/pdbsum/1txd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1txd ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/ARHGC_HUMAN ARHGC_HUMAN] Note=A chromosomal aberration involving ARHGEF12 may be a cause of acute leukemia. Translocation t(11;11)(q23;23) with MLL.
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== Function ==
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[https://www.uniprot.org/uniprot/ARHGC_HUMAN ARHGC_HUMAN] May play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13). Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPase and may act as GTPase-activating protein (GAP) for GNA12 and GNA13.<ref>PMID:11094164</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/tx/1txd_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=1txd 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 myeloid OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604763 604763]]
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*[[Rho guanine nucleotide exchange factor 3D structures|Rho guanine nucleotide exchange factor 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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1TXD is a [http://en.wikipedia.org/wiki/Single_protein 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=1TXD OCA].
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__TOC__
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</StructureSection>
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==Reference==
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Structural determinants of RhoA binding and nucleotide exchange in leukemia-associated Rho guanine-nucleotide exchange factor., Kristelly R, Gao G, Tesmer JJ, J Biol Chem. 2004 Nov 5;279(45):47352-62. Epub 2004 Aug 25. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15331592 15331592]
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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: Gao, G.]]
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[[Category: Gao G]]
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[[Category: Kristelly, R.]]
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[[Category: Kristelly R]]
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[[Category: Tesmer, J.J.]]
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[[Category: Tesmer JJ]]
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[[Category: beta sandwich (ph)]]
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[[Category: helical bundle (dh)]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 16:58:44 2008''
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Current revision

Crystal Structure of the DH/PH domains of Leukemia-associated RhoGEF

PDB ID 1txd

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