Figure 1.

Structural effect of inhibitor binding and differences in the YM-254890/FR900359 binding site between G_q and G_s. A, superimposition of YM-254890–bound Gα_q (dark orange carbon atoms and cartoon representation, YM-254890 and GDP as sticks; PDB code 3AH8) and the GDP/Al⁴⁺-activated Gα_q without inhibitor (light orange carbon atoms and cartoon representation; PDB code 5DO9) based on the GTPase domain shows a 2.8-Å inhibitor-induced shift in the relative location of the helical domain (double arrow). B, superimposition of the inactive GDP-bound G_s (purple carbon atoms and cartoon; PDB code 6EG8) and the GTPγS-activated G_s (cyan carbon atoms and cartoon; PDB code 1AZT) shows practically identical relative location of the GTPase and helical domains. C, the depsipeptide-binding site in YM-254890-bound Gα_q (as in A) superimposed on a homology model of Gα_s (gray carbon atoms and cartoon) highlighting (sticks) the binding site residues (within 6 Å and side chains pointing toward YM-254890) that differ between Gα_q and Gα_s. Val-182/Cys-186 is included, as it is part of a hydrophobic network of amino acids having close vdW contact with each other and with YM-254890 (dotted lines). Labels indicate one-letter amino acid codes and numbers in G_q/G_s. D, sequence alignment of the YM-254890–binding site region in Gα_q and Gα_s, highlighting differing binding site residues (green). Residues in the red box are not part of the binding site but the hydrophobic network. Sequence numbers are from G_q.