Figure 1.

Structural overview of insulin. A, sequence of insulin with disulfide bridges in black. Tyr^B26 is highlighted in black; the present Tyr^B26 → Trp substitution is orange; and modifications in pI-shifted clinical analog glargine in purple. Our semisynthetic pI-shifted analog contained Orn (green) instead of Lys or Arg. B, structure of an insulin monomer; the A chain is shown in black and B chain in green. Tyr^B26 is red, whereas Phe^B24 and Tyr^B16 are blue (PDB code 4INS). C, structure of zinc-coordinated insulin hexamer (T₆ state), a trimer of dimers; Tyr^B26, Phe^B24, and Tyr^B16 are color-coded as in B. D, stereo view showing Tyr^B26 (sticks) in a cavity within insulin dimer (extracted from T₃R^f₃ hexamer, PDB code 1TRZ). E, corresponding stick model with residues labeled.