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Wide Turn Diversity in Protein Transmembrane Helices Implications for G-Protein-Coupled Receptor and Other Polytopic Membrane Protein Structure and Function

Computational and Structural Biology Division (R.P.R.) and Molecular Cardiology (A.A.F., G.B., R.M.G.) Divisions, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; and Department of Pharmacology, School of Medical Sciences, University of New South Wales, Kensington, New South Wales, Australia (A.A.F.)

Previously, we showed that perturbations of protein transmembrane helices are manifested as one of three types of noncanonical structures (wide turns, tight turns, and kinks), which, compared with -helices, are evident by distinctive C_iC_x distances. In this study, we report the analysis of more than 3000 transmembrane helices in 244 crystal structures from which we identified 70 wide turns (29 proline- and 41 nonproline-induced). Based on differences in the C_iC_i-4 and C_iC_i-5 profiles, we show that wide turns can be subclassified into three distinct subclasses (W₁, W₂, and W₃) that differ with regard to the number and position of backbone i i-5 H-bonds formed N-terminal to the perturbing or signature proline or nonproline residue. Although wide turns generally produce changes in helical direction of 20° to 30° and a lateral shift in the helical axis, some of the W₃ subclass are associated with changes of <5°. We also show that the distinct architectural features of wide turns allow the carbonyl bond of the i-4th residue, which is located on the widened loop of a wide turn, to be directed away from the helical axis. This provides regions of flexibility within helical regions allowing, for example, unique opportunities for interhelical H-bonding, including interactions with glycine zipper motifs, and for ion and cofactor binding. Furthermore, differences in wide-turn subtype usage by related protein family members, such as the G-protein-coupled receptors rhodopsin and the β2-adrenergic receptor, can significantly affect the orientation and position of residues critical for ligand binding and receptor activation.

Address correspondence to: Dr. Robert M. Graham, 384 Victoria Street, Darlinghurst, NSW 2010, Australia. E-mail: b.graham{at}victorchang.edu.au