scholarly journals Differential Protein Dynamics of Regulators of G-Protein Signaling: Role in Specificity of Small-Molecule Inhibitors

2018 ◽  
Vol 140 (9) ◽  
pp. 3454-3460 ◽  
Author(s):  
Vincent S. Shaw ◽  
Hossein Mohammadiarani ◽  
Harish Vashisth ◽  
Richard R. Neubig
Keyword(s):  
Protein Dynamics ◽  
G Protein ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Differential 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 Reversible, Allosteric Small-Molecule Inhibitors of Regulator of G Protein Signaling Proteins

2010 ◽  
Vol 78 (3) ◽  
pp. 524-533 ◽  
Author(s):  
Levi L. Blazer ◽  
David L. Roman ◽  
Alfred Chung ◽  
Martha J. Larsen ◽  
Benjamin M. Greedy ◽  
...  
Keyword(s):  
G Protein ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
G Protein Signaling ◽  
Signaling Proteins ◽  
Protein Signaling

scholarly journals Small Molecule Inhibitors of Regulators of G Protein Signaling (RGS) Proteins

2011 ◽  
Vol 3 (2) ◽  
pp. 146-150 ◽  
Author(s):  
Emma M. Turner ◽  
Levi L. Blazer ◽  
Richard R. Neubig ◽  
Stephen M. Husbands
Keyword(s):  
G Protein ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
G Protein Signaling ◽  
Rgs Proteins ◽  
Protein Signaling

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 Rubsicolins are naturally occurring G-protein-biased delta opioid receptor peptides

2018 ◽  
Author(s):  
Robert J. Cassell ◽  
Kendall L. Mores ◽  
Breanna L. Zerfas ◽  
Amr H. Mahmoud ◽  
Markus A. Lill ◽  
...  
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Small Molecule ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Naturally Occurring ◽  
Δ Opioid Receptor ◽  
The Impact ◽  
G Protein Coupled ◽  
Deltorphin Ii

AbstractThe impact that β-arrestin proteins have on G-protein-coupled receptor trafficking, signaling and physiological behavior has gained much appreciation over the past decade. A number of studies have attributed the side effects associated with the use of naturally occurring and synthetic opioids, such as respiratory depression and constipation, to excessive recruitment of β-arrestin. These findings have led to the development of biased opioid small molecule agonists that do not recruit β-arrestin, activating only the canonical G-protein pathway. Similar G-protein biased small molecule opioids have been found to occur in nature, particularly within kratom, and opioids within salvia have served as a template for the synthesis of other G-protein-biased opioids. Here, we present the first report of naturally occurring peptides that selectively activate G-protein signaling pathways with minimal β-arrestin recruitment. We find that rubiscolin peptides, which are produced as cleavage products of the plant protein rubisco, bind to and activate G-protein signaling at δ opioid receptors. However, unlike the naturally occurring δ opioid peptides leu-enkephalin and deltorphin II, the rubiscolin peptides only very weakly recruit β-arrestin 2 and have undectable recruitment of β-arrestin 1 at the δ opioid receptor.

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