Journal of Biological Chemistry
Protein Structure and FoldingDeciphering a Molecular Mechanism of Neonatal Diabetes Mellitus by the Chemical Synthesis of a Protein Diastereomer, [d-AlaB8]Human Proinsulin*
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This work was supported, in whole or in part, by National Institutes of Health Grant R01 DK069764 from the NIDDK (to M. A. W.) with a subcontract to S. B. Kent (University of Chicago). M. A. W. has equity in Thermalin Diabetes, LLC (Cleveland, OH) where he serves as Chief Scientific Officer and has also been a consultant to Merck Research Laboratories and DEKA Research and Development Corp.
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A suite of four co-crystal structures has recently been reported depicting insulin bound to fragments of the IR ectodomain at 3.9-Å resolution (58). Although electron density was not observed for residues B1-B6, three of the four structures appear to exhibit a positive φ dihedral angle at GlyB8; the fourth exhibits a negative φ angle at B8 but would be precluded from adopting a positive value by a bound Fab fragment (M. C. Lawrence, personal communication). It is thus not known to what extent the bound conformation of insulin may resemble, in its N-terminal B-chain segment, the classical R state of insulin.
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Supported in part by the American Diabetes Association.
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The abbreviations used are:
- DM
diabetes mellitus
- Boc
tert-butoxycarbonyl
- ER
endoplasmic reticulum
- IR
insulin receptor
- PDI
protein-disulfide isomerase
- MPAA
4-mercaptophenylacetic acid
- Thz
1,3-thiazolidine-4-carboxo
- GdnHCl
guanidine hydrochloride.