scholarly journals Investigating Regulator of G‐protein Signaling (RGS) Protein Dynamics by Hydrogen/Deuterium Exchange

2017 ◽  
Vol 31 (S1) ◽  
Author(s):  
Vincent S. Shaw ◽  
Anthony L. Schilmiller ◽  
Harish Vashisth ◽  
Richard R. Neubig
Keyword(s):  
Protein Dynamics ◽  
G Protein ◽  
Deuterium Exchange ◽  
G Protein Signaling ◽  
Hydrogen Deuterium Exchange ◽  
Protein Signaling ◽  
Hydrogen Deuterium ◽  
Rgs Protein

scholarly journals Interplay of cysteine exposure and global protein dynamics in small-molecule recognition by a regulator of G-protein signaling protein

2018 ◽  
Vol 87 (2) ◽  
pp. 146-156 ◽  
Author(s):  
Mohammadjavad Mohammadi ◽  
Hossein Mohammadiarani ◽  
Vincent S. Shaw ◽  
Richard R. Neubig ◽  
Harish Vashisth
Keyword(s):  
Protein Dynamics ◽  
G Protein ◽  
Small Molecule ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Signaling Protein ◽  
Molecule Recognition

scholarly journals Screen Targeting Lung and Prostate Cancer Oncogene Identifies Novel Inhibitors of RGS17 and Problematic Chemical Substructures

2018 ◽  
Vol 23 (4) ◽  
pp. 363-374 ◽  
Author(s):  
Christopher R. Bodle ◽  
Josephine H. Schamp ◽  
Joseph B. O’Brien ◽  
Michael P. Hayes ◽  
Meng Wu ◽  
...  
Keyword(s):  
G Protein ◽  
Small Molecule ◽  
High Throughput Screening ◽  
Biochemical Characterization ◽  
Parent Compound ◽  
Receptor Activation ◽  
G Protein Signaling ◽  
Conservation Of Resources ◽  
Protein Signaling ◽  
Rgs Protein

Regulator of G protein signaling (RGS) proteins temporally regulate heterotrimeric G protein signaling cascades elicited by G protein–coupled receptor activation and thus are essential for cell homeostasis. The dysregulation of RGS protein expression has been linked to several pathologies, spurring discovery efforts to identify small-molecule inhibitors of these proteins. Presented here are the results of a high-throughput screening (HTS) campaign targeting RGS17, an RGS protein reported to be inappropriately upregulated in several cancers. A screen of over 60,000 small molecules led to the identification of five hit compounds that inhibit the RGS17-Gαo protein-protein interaction. Chemical and biochemical characterization demonstrated that three of these hits inhibited the interaction through the decomposition of parent compound into reactive products under normal chemical library storage/usage conditions. Compound substructures susceptible to decomposition are reported and the decomposition process characterized, adding to the armamentarium of tools available to the screening field, allowing for the conservation of resources in follow-up efforts and more efficient identification of potentially decomposed compounds. Finally, analogues of one hit compound were tested, and the results establish the first ever structure-activity relationship (SAR) profile for a small-molecule inhibitor of RGS17.

scholarly journals Evidence for a Role of the Regulator of G-Protein Signaling Protein CPRGS-1 in Gα Subunit CPG-1-Mediated Regulation of Fungal Virulence, Conidiation, and Hydrophobin Synthesis in the Chestnut Blight Fungus Cryphonectria parasitica

2004 ◽  
Vol 3 (6) ◽  
pp. 1454-1463 ◽  
Author(s):  
Gerrit C. Segers ◽  
Jerome C. Regier ◽  
Donald. L. Nuss
Keyword(s):  
G Protein ◽  
Pathogenic Fungus ◽  
Aerial Mycelium ◽  
Cryphonectria Parasitica ◽  
Chestnut Blight ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Fungal Virulence ◽  
Chestnut Blight Fungus ◽  
Rgs Protein

ABSTRACT We previously reported that the chestnut blight fungus Cryphonectria parasitica expresses at least three G-protein α subunits and that Gα subunit CPG-1 is essential for regulated growth, pigmentation, sporulation, and virulence. We now report the cloning and characterization of a C. parasitica regulator of G-protein signaling (RGS) protein, CPRGS-1. The phylogenetic relationship of CPRGS-1 to orthologs from other fungi was inferred and found to be generally concordant with species relationships based on 18S ribosomal sequences and on morphology. However, Hemiascomycotine RGS branch lengths in particular were longer than for their 18S sequence counterparts, which correlates with functional diversification in the signaling pathway. Deletion of cprgs-1 resulted in reduced growth, sparse aerial mycelium, and loss of pigmentation, sporulation, and virulence. Disruption of cprgs-1 was also accompanied by a severe posttranscriptional reduction in accumulation of CPG-1 and Gβ subunit CPGB-1 and severely reduced expression of the hydrophobin-encoding gene cryparin. The changes in phenotype, cryparin expression, and CPGB-1 accumulation resulting from cprgs-1 gene deletion were also observed in a strain containing a mutationally activated copy of CPG-1 but not in strains containing constitutively activated mutant alleles of the other two identified Gα subunits, CPG-2 and CPG-3. Furthermore, cprgs-1 transcript levels were increased in the activated CPG-1 strain but were unaltered in activated CPG-2 and CPG-3 strains. The results strongly suggest that CPRGS-1 is involved in regulation of Gα subunit CPG-1-mediated signaling and establish a role for a RGS protein in the modulation of virulence, conidiation, and hydrophobin synthesis in a plant pathogenic fungus.

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