Abstract
Regulators of G‐protein signaling (RGS) proteins regulate G‐protein coupled receptor (GPCR) signal transduction cascades by acting as GTPase accelerating proteins upon binding activated Gα subunits. RGS proteins express in cell‐type specific manners, couple to and regulate specific GPCRs, and are overexpressed in pathologies from cancer to Parkinson's disease, and as such, they are an attractive drug target. Small‐molecule RGS4 inhibitor screens have yielded a number of covalent thiol modifiers that act allosterically at Cys148, far from the RGS/Gα interface. Thus far, the structural basis of RGS4 inhibition is unknown, so in the current study we investigate the structural consequence of RGS4's covalent modification that leads to inhibition of Gα binding. To ensure structure homogeneity, we expressed in and purified from Escherichia coli recombinant RGS4 with cysteines removed, except Cys148, and obtained nuclear magnetic resonance spectra for free and modified RGS4. Overlaid 15N‐1H HSQC spectra show significant changes in RGS4 structure upon small molecule modification. These data provide further evidence for a region that may be amenable for rational drug design. Project funded by 5T32GM067795‐08.
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