4xh9

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==CRYSTAL STRUCTURE OF HUMAN RHOA IN COMPLEX WITH DH/PH FRAGMENT OF THE GUANINE NUCLEOTIDE EXCHANGE FACTOR NET1==
==CRYSTAL STRUCTURE OF HUMAN RHOA IN COMPLEX WITH DH/PH FRAGMENT OF THE GUANINE NUCLEOTIDE EXCHANGE FACTOR NET1==
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<StructureSection load='4xh9' size='340' side='right' caption='[[4xh9]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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<StructureSection load='4xh9' size='340' side='right'caption='[[4xh9]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4xh9]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XH9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XH9 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4xh9]] is a 4 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=4XH9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XH9 FirstGlance]. <br>
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</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4xh9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xh9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4xh9 RCSB], [http://www.ebi.ac.uk/pdbsum/4xh9 PDBsum]</span></td></tr>
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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&#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=4xh9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xh9 OCA], [https://pdbe.org/4xh9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xh9 RCSB], [https://www.ebi.ac.uk/pdbsum/4xh9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xh9 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/ARHG8_HUMAN ARHG8_HUMAN]] Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPase. May be involved in activation of the SAPK/JNK pathway Stimulates genotoxic stress-induced RHOB activity in breast cancer cells leading to their cell death.<ref>PMID:21373644</ref> [[http://www.uniprot.org/uniprot/RHOA_HUMAN RHOA_HUMAN]] Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers. Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis. Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion. Serves as a target for the yopT cysteine peptidase from Yersinia pestis, vector of the plague, and Yersinia pseudotuberculosis, which causes gastrointestinal disorders. Stimulates PKN2 kinase activity. May be an activator of PLCE1. Activated by ARHGEF2, which promotes the exchange of GDP for GTP. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization.<ref>PMID:8910519</ref> <ref>PMID:9121475</ref> <ref>PMID:12900402</ref> <ref>PMID:16103226</ref> <ref>PMID:16236794</ref> <ref>PMID:19934221</ref> <ref>PMID:20937854</ref> <ref>PMID:20974804</ref>
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[https://www.uniprot.org/uniprot/ARHG8_HUMAN ARHG8_HUMAN] Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPase. May be involved in activation of the SAPK/JNK pathway Stimulates genotoxic stress-induced RHOB activity in breast cancer cells leading to their cell death.<ref>PMID:21373644</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The GTPase RhoA is a major player in many different regulatory pathways. RhoA catalyzes GTP hydrolysis, and its catalysis is accelerated when RhoA forms heterodimers with proteins of the guanine nucleotide exchange factor (GEF) family. Neuroepithelial cell transforming gene 1 (Net1) is a RhoA-interacting GEF implicated in cancer, but the structural features supporting the RhoA/Net1 interaction are unknown. Taking advantage of a simple production and purification process, here we solved the structure of a RhoA/Net1 heterodimer with X-ray crystallography at 2-A resolution. Using a panel of several techniques, including molecular dynamics simulations, we characterized the RhoA/Net1 interface. Moreover, deploying an extremely simple peptide-based scanning approach, we found that short peptides (penta- to nonapeptides) derived from the protein/protein interaction region of RhoA could disrupt the RhoA/Net1 interaction and thereby diminish the rate of nucleotide exchange. The most inhibitory peptide, EVKHF, spanning residues 102-106 in the RhoA sequence, displayed an IC50 of approximately 100 mum without further modifications. The peptides identified here could be useful in further investigations of the RhoA/Net1 interaction region. We propose that our structural and functional insights might inform chemical approaches for transforming the pentapeptide into an optimized pseudopeptide that antagonizes Net1-mediated RhoA activation with therapeutic anticancer potential.
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A structural study of the complex between neuroepithelial cell transforming gene 1 (Net1) and RhoA reveals a potential anticancer drug hot spot.,Petit AP, Garcia-Petit C, Bueren-Calabuig JA, Vuillard LM, Ferry G, Boutin JA J Biol Chem. 2018 Jun 8;293(23):9064-9077. doi: 10.1074/jbc.RA117.001123. Epub, 2018 Apr 25. PMID:29695506<ref>PMID:29695506</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4xh9" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Rho GTPase 3D structures|Rho GTPase 3D structures]]
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*[[Rho guanine nucleotide exchange factor 3D structures|Rho guanine nucleotide exchange factor 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: BOUTIN, J A]]
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[[Category: Homo sapiens]]
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[[Category: FERRY, G]]
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[[Category: Large Structures]]
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[[Category: GARCIA, C]]
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[[Category: Boutin JA]]
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[[Category: PETIT, P]]
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[[Category: Ferry G]]
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[[Category: VUILLARD, L]]
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[[Category: Garcia C]]
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[[Category: Activator]]
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[[Category: Petit P]]
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[[Category: Guanine nucleotide exchange factor]]
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[[Category: Vuillard L]]
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[[Category: Rhoa gtpase]]
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[[Category: Signaling protein]]
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Current revision

CRYSTAL STRUCTURE OF HUMAN RHOA IN COMPLEX WITH DH/PH FRAGMENT OF THE GUANINE NUCLEOTIDE EXCHANGE FACTOR NET1

PDB ID 4xh9

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