Journal
SCIENCE
Volume 312, Issue 5772, Pages 443-446Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1120378
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Funding
- NCI NIH HHS [R01 CA132317] Funding Source: Medline
- NHLBI NIH HHS [HL-T3207949, R01 HL080706, R01 HL080706-10, R01 HL080706-11, HL080706] Funding Source: Medline
- NIDA NIH HHS [T32DA07232, K05-DA00360] Funding Source: Medline
- NIGMS NIH HHS [R01 GM054597-09, R01 GM054597, GM60286] Funding Source: Medline
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G protein beta gamma subunits have potential as a target for therapeutic treatment of a number of diseases. We performed virtual docking of a small-molecule library to a site on G beta gamma subunits that mediates protein interactions. We hypothesized that differential targeting of this surface could allow for selective modulation of G beta gamma subunit functions. Several compounds bound to G beta gamma subunits with affinities from 0.1 to 60 mu M and selectively modulated functional G beta gamma-protein-protein interactions in vitro, chemotactic peptide signaling pathways in HL-60 leukocytes, and opioid receptor-dependent analgesia in vivo. These data demonstrate an approach for modulation of G protein-coupled receptor signaling that may represent an important therapeutic strategy.
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