Abstract:
:X-ray studies on human insulins prepared by semisynthetic and biosynthetic methods have recently been undertaken. Human insulin differs from porcine insulin only at the COOH terminus of the B-chain. The present study reports the crystal structure of 4-zinc human insulin, which is used clinically as a slow-acting preparation. The structure has been refined, using 1.85-A resolution data, to a residual of 0.173. The unit cell is rhombohedral, space group R3, with hexagonal cell constants a = 80.953 and c = 37.636 A, and it is nearly isomorphous with that of 4-zinc porcine insulin. As a result of a conformational change of the first eight residues of the B-chain of molecule 1 from an extended conformation observed in the 2-zinc structure to an alpha-helical one, the coordination around one of the zinc ions on the 3-fold axis has changed, an additional zinc ion in a general position is bound by the hexamer, and additional hydrogen-bonded interactions help stabilize dimer and hexamer formation. Unlike the surface of the 2-zinc insulin hexamer, which possesses a shallow depression containing a zinc ion and its coordinating water molecules, the 4-zinc human insulin hexamer contains a zinc and chloride ion at the bottom of an 8-A tunnel produced by three parallel alpha-helices. These alpha-helices shield the zinc ion from the environment, decreasing the rate of dissociation of the hexamer, and provide an explanation for the slow-acting aspect of the 4-zinc crystalline form.
journal_name
Proc Natl Acad Sci U S Aauthors
Smith GD,Swenson DC,Dodson EJ,Dodson GG,Reynolds CDdoi
10.1073/pnas.81.22.7093subject
Has Abstractpub_date
1984-11-01 00:00:00pages
7093-7issue
22eissn
0027-8424issn
1091-6490journal_volume
81pub_type
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