Extended Data Figure 2: Effect of ligand head group substitution on hydrogen bond network involving V172(4.56) in β1AR.
From: Backbone NMR reveals allosteric signal transduction networks in the β1-adrenergic receptor
a, Sequence alignment of turkey β1AR and human adrenoreceptors around position 4.56 in TM4 showing the conserved proline at position 4.60. b, Schematic representation of the hydrogen bond network between TM4 and TM5 involving V172(4.56) in β1AR. The hydrogen bond network (orange dotted lines) originates at the carbonyl of V172(4.56) and connects to TM5 via two water molecules (w1 and w2, red asterisks). c, Left, phi and psi dihedral angles (averages and standard deviations in case of multiple chains) in TM4 between residues 4.48 and 4.61 for different complexes of β1AR (ligand, PDB code [chain]: carvedilol, 4AMJ [A,B]; cyanopindolol, 2VT4 [B,D] and 4BVN [A]; dobutamine, 2Y00 [A,B] and 2Y01 [A,B]; isoprenaline, 2Y03 [A,B]). V165(4.49) and V172(4.56), for which 1H–15N resonances could be observed, are shown on a green and red background, respectively. c, Right, average of the 1H–15N resonance positions for V165(4.49, green) and V172(4.56, red). The phi and psi values of V172(4.56) are distorted from the normal helical angles due to the loss of the intra-helical hydrogen bond to P176(4.60). Together with the loss of the canonical hydrogen bond, this strongly shifts both the 1H and 15N chemical shifts of V172(4.56) towards smaller p.p.m. values relative to V165(4.49), which has normal, helical phi and psi angles. d, Partial views of the crystal structures of the carvedilol complex (PDB code 4AMJ), the isoprenaline complex (PDB code 2Y03) and a docking model of the atenolol complex based on the cyanopindolol complex crystal structure (PDB code 4BVN). In the carvedilol complex, one water molecule (w2) forms a hydrogen bond network between the carbonyl oxygen of V172(4.56) and the side chains of S211(5.43) and S215(5.461). In the isoprenaline complex, the side chains of S211(5.43) and S215(5.461) are rotated and form hydrogen bonds to the catechol hydroxyl groups of isoprenaline. In this structure, no water molecule is observed at the equivalent position of w2. In the atenolol complex, the para-substituted acetamide of the ligand head ring (dashed circle) inserts between S211(5.43) and S215(5.461) and disturbs the interface between TM3 and TM5 near V172(4.56) (solid circle).
