Fig. 2.

Conformation of ICL2 and ionic lock motif in D3R and other GPCR structures. As also seen in (A) the inactive Rhodopsin structure (PDB ID: 1U19), the conserved ionic lock motif D[E]RY is in a “locked” conformation in (B) the D3R structure, i.e. with a salt bridge formed between Arg128^3.50 and Glu324^6.30. In addition, the side chain of Tyr138 in the ICL2 α-helix of the D3R is inserted into the seven-TM bundle forming hydrogen bonds with Thr64^2.39, Arg128^3.50 and Asp127^3.49 (distances 3.0 Å, 3.2 Å and 3.2 Å, respectively), potentially stabilizing the ionic lock. There is no salt bridge between Arg3.50-Glu6.30 (and hence the “ionic lock” is “broken”) in other crystal structures of GPCR shown in panels (C) β₁AR (PDB ID: 2VT4), (D) β₂AR (PDB ID: 2RH1), (E) A_2AAR (PDB ID: 3EML). In both the β₁AR and A_2AAR structures, however, the corresponding Tyr residue in ICL2 that aligns to Tyr138 in D3R forms two hydrogen bonds with the Asp^3.49 and Arg^3.50 side chains even in the absence of the closed ionic lock conformation. Salt bridges are shown as red dashed lines, and hydrogen bond interactions are shown as blue dashed lines.