4xh9

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

spinqualitylabelsall models 4xh9, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4xh9 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function 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. Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Rho GTPase 3D structures Rho guanine nucleotide exchange factor 3D structures

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