TY - JOUR T1 - Suramin Disrupts Receptor-G Protein Coupling by Blocking Association of G Protein α and βγ Subunits JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 191 LP - 198 DO - 10.1124/jpet.104.078311 VL - 313 IS - 1 AU - Wen-Cheng Chung AU - John C. Kermode Y1 - 2005/04/01 UR - http://jpet.aspetjournals.org/content/313/1/191.abstract N2 - Most drugs target a receptor for a hormone or neurotransmitter. A newer strategy for drug development is to target a downstream signaling element, such as the G protein associated with a receptor. Suramin is considered a lead compound targeting this moiety. It inhibits binding of guanosine 5′-O-(3-thiotriphosphate) (GTPγS) to G proteins and reduces agonist binding to G protein-coupled receptors. Suramin is thought to uncouple the G protein from its associated receptor, although there is no direct evidence for this mechanism. We have now examined the effect of suramin on G protein signaling for the vasoactive intestinal peptide (VIP) receptor in lung. The primary experimental strategy was a two-step cross-linking reaction that covalently captures the VIP-receptor-G protein ternary complex. Such cross-linking provided the first direct evidence that suramin physically disrupts receptor-G protein coupling. We investigated how this uncoupling relates to the inhibition of GTPγS binding. Suramin indiscriminately hindered the dissociation of various guanine nucleotides from the G protein, implying that its action is not allosteric. Further cross-linking studies suggested that suramin does not obstruct the receptor docking site directly but appears to block the interface between G protein α and βγ subunits. Observations with a purified system of recombinant G protein subunits without a receptor yielded direct evidence that suramin suppresses the association between these subunits. This action can explain how it both disrupts receptor-G protein coupling and inhibits guanine nucleotide release. The improved understanding of suramin's action advances the development of selective inhibitors of G protein signaling. The American Society for Pharmacology and Experimental Therapeutics ER -