3KQ6

Enhancing the Therapeutic Properties of a Protein by a Designed Zinc-Binding Site, Structural principles of a novel long-acting insulin analog

Summary for 3KQ6

• Entry DOI: 10.2210/pdb3kq6/pdb
• Related: 1RWE
• Descriptor: Insulin A chain, Insulin B chain, ZINC ION, ... (6 entities in total)
• Functional Keywords: zinc-binding site, long-acting insulin analog, receptor binding, carbohydrate metabolism, cleavage on pair of basic residues, diabetes mellitus, disease mutation, disulfide bond, glucose metabolism, hormone, pharmaceutical, secreted
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted: P01308 P01308
• Total number of polymer chains: 4
• Total formula weight: 12088.70

Authors

Wan, Z.L.,Hu, S.Q.,Whittaker, L.,Phillips, N.B.,Whittake, J.,Ismail-Beigi, F.,Weiss, M.A. (deposition date: 2009-11-17, release date: 2010-02-23, Last modification date: 2024-11-06)

Primary citation

Phillips, N.B.,Wan, Z.L.,Whittaker, L.,Hu, S.Q.,Huang, K.,Hua, Q.X.,Whittaker, J.,Ismail-Beigi, F.,Weiss, M.A.
Supramolecular protein engineering: design of zinc-stapled insulin hexamers as a long acting depot.
J.Biol.Chem., 285:11755-11759, 2010

PubMed Abstract: Bottom-up control of supramolecular protein assembly can provide a therapeutic nanobiotechnology. We demonstrate that the pharmacological properties of insulin can be enhanced by design of "zinc staples" between hexamers. Paired (i, i+4) His substitutions were introduced at an alpha-helical surface. The crystal structure contains both classical axial zinc ions and novel zinc ions at hexamer-hexamer interfaces. Although soluble at pH 4, the combined electrostatic effects of the substitutions and bridging zinc ions cause isoelectric precipitation at neutral pH. Following subcutaneous injection in a diabetic rat, the analog effected glycemic control with a time course similar to that of long acting formulation Lantus. Relative to Lantus, however, the analog discriminates at least 30-fold more stringently between the insulin receptor and mitogenic insulin-like growth factor receptor. Because aberrant mitogenic signaling may be associated with elevated cancer risk, such enhanced specificity may improve safety. Zinc stapling provides a general strategy to modify the pharmacokinetic and biological properties of a subcutaneous protein depot.

PubMed: 20181952
DOI: 10.1074/jbc.C110.105825

Experimental method

X-RAY DIFFRACTION (1.9 Å)