PubMed · 4353826
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M B Davidson, A J Van Herle. 1973-09-27. Technical problems with agarose-hormone linkage.. https://doi.org/10.1056/nejm197309272891317
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The determination of deshexapeptide (B25-B30) insulin (DHI) was divided into two steps. At the first step, the rough structure model of DHI molecule was determined by using the molecular replacement method associated with the molecular close-packing method at 0.30 nm resolution based on the reflection data collected on four-cycle diffractometer. At the second step, the DHI model was adjusted and refined at 0.25 nm resolution based on the data collected on Area Detector. 40 water molecules were determined during the refinement, the final R-factor is 0.185 with R.M.S. deviation of 0.002 nm for bond lengths and 1.9 degrees for bond angles. The differences in conformation and function of DHI with other insulin analogues were compared and discussed.
Molecular dynamics simulations were carried out on an insulin crosslinked between the N-terminal A chain and the C-terminal B chain to form a so-called mini-proinsulin: N alpha-A1-N epsilon-B29-diaminosuberoyl insulin (DASI). To investigate the influence of crosslinking on the dynamics of the insulin moiety, the bridge was removed from a transient DASI structure and simulation was carried on independently with the then unlinked (ULKI) as well as with the crosslinked species. The effects of crystal packing and quaternary interactions were checked by simulating both types of monomers and dimers known from the hexamer structure. All simulations were compared to previous ones of native insulin. DASI shows general similarity to the native simulations in most parts of the structure. Deviations are visible in the segments to which the bridge is directly connected, i.e. their flexibility is reduced. Upon removal of the bridge the ULKI simulations reapproach those of native insulin. The influence of the bridge spreads over the whole molecule, but all of its main structural features remain intact. The simulations suggest that the displacement of the C-terminal B chain of native insulin, considered important for receptor interaction, is prevented by the bridge, which also partially shields some binding residues. This is in accordance with the poor biological potency of A1-B29-crosslinked insulins.
Although the structure of insulin is known in great detail, that of proinsulin has been little investigated, except for a few CD and NMR studies. The secondary structures of human proinsulin are now compared with those of insulin by Fourier Transformed Infrared (FTIR) studies. The deconvolved and second derivative spectra of proinsulin and insulin in the amide I' band region are closely similar with peaks corresponding to alpha-helix, irregular helix, and 3(10) helix at nearly identical positions. For both proteins, the relative contents of the above structures as calculated from the peak areas are in good agreement with the values obtained from the known structure of crystalline porcine insulin. However, compared with insulin, proinsulin has markedly more unordered structures as indicated by the area under the peak at 1643.4 cm-1. In addition, both peak positions and relative areas for turn structure of the prohormone are different from those for insulin. It appears from the above that the A-and B-chain segments of proinsulin and insulin are similar in their secondary structures, especially in helices. The C-chain segment is largely unordered except in a few beta-turns.