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Structural Studies of RGS Inhibitors
Author(s) -
Higgins Colin Anthony,
Fuentes Ernesto,
Roman David
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1095.9
Subject(s) - g protein coupled receptor , biophysics , g protein , small molecule , microbiology and biotechnology , gtpase , chemistry , biochemistry , biology , signal transduction , computational biology
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, regulate specific GPCRs, and are overexpressed in pathologies from cancer to Parkinson's disease. As such, they are attractive drug targets. 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. We purified recombinant RGS4 from Escherichia coli and obtained nuclear magnetic resonance spectra for free and modified RGS4. Overlaid 15 N‐ 1 H HSQC spectra show significant changes in RGS4 structure upon small molecule modification. Data from circular dichroism, dynamic light scattering, and other techniques provide further evidence that the pocket may be amenable for rational drug design. Project funded by 5T32GM067795–08 and pre‐doctoral fellowship from AFPE.