2KQP
NMR Structure of Proinsulin
Summary for 2KQP
| Entry DOI | 10.2210/pdb2kqp/pdb |
| NMR Information | BMRB: 16608 |
| Descriptor | Insulin (1 entity in total) |
| Functional Keywords | proinsulin, carbohydrate metabolism, cleavage on pair of basic residues, diabetes mellitus, disease mutation, disulfide bond, glucose metabolism, hormone, pharmaceutical, secreted |
| Biological source | Homo sapiens (human) |
| Cellular location | Secreted: P01308 |
| Total number of polymer chains | 1 |
| Total formula weight | 9379.58 |
| Authors | Yang, Y.,Hua, Q.X.,Mackin, R.B.,Weiss, M.A. (deposition date: 2009-11-12, release date: 2010-01-26, Last modification date: 2024-10-30) |
| Primary citation | Yang, Y.,Hua, Q.X.,Liu, J.,Shimizu, E.H.,Choquette, M.H.,Mackin, R.B.,Weiss, M.A. Solution structure of proinsulin: connecting domain flexibility and prohormone processing. J.Biol.Chem., 285:7847-7851, 2010 Cited by PubMed Abstract: The folding of proinsulin, the single-chain precursor of insulin, ensures native disulfide pairing in pancreatic beta-cells. Mutations that impair folding cause neonatal diabetes mellitus. Although the classical structure of insulin is well established, proinsulin is refractory to crystallization. Here, we employ heteronuclear NMR spectroscopy to characterize a monomeric analogue. Proinsulin contains a native-like insulin moiety (A- and B-domains); the tethered connecting (C) domain (as probed by {(1)H}-(15)N nuclear Overhauser enhancements) is progressively less ordered. Although the BC junction is flexible, residues near the CA junction exhibit alpha-helical-like features. Relative to canonical alpha-helices, however, segmental (13)C(alpha/beta) chemical shifts are attenuated, suggesting that this junction and contiguous A-chain residues are molten. We propose that flexibility at each C-domain junction facilitates prohormone processing. Studies of protease SPC3 (PC1/3) suggest that C-domain sequences contribute to cleavage site selection. The structure of proinsulin provides a foundation for studies of insulin biosynthesis and its impairment in monogenic forms of diabetes mellitus. PubMed: 20106974DOI: 10.1074/jbc.C109.084921 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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