6CK2
Insulin analog containing a YB26W mutation
Summary for 6CK2
| Entry DOI | 10.2210/pdb6ck2/pdb |
| Descriptor | Insulin A chain, Insulin B chain, ZINC ION, ... (6 entities in total) |
| Functional Keywords | long-acting, basal, therapeutic, peptide hormone, diabetes, biomolecular engineering, hormone |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 11911.69 |
| Authors | Rege, N.K.,Yee, V.C.,Weiss, M.A. (deposition date: 2018-02-27, release date: 2018-06-13, Last modification date: 2023-10-04) |
| Primary citation | Rege, N.K.,Wickramasinghe, N.P.,Tustan, A.N.,Phillips, N.F.B.,Yee, V.C.,Ismail-Beigi, F.,Weiss, M.A. Structure-based stabilization of insulin as a therapeutic protein assembly via enhanced aromatic-aromatic interactions. J. Biol. Chem., 293:10895-10910, 2018 Cited by PubMed Abstract: Key contributions to protein structure and stability are provided by weakly polar interactions, which arise from asymmetric electronic distributions within amino acids and peptide bonds. Of particular interest are aromatic side chains whose directional π-systems commonly stabilize protein interiors and interfaces. Here, we consider aromatic-aromatic interactions within a model protein assembly: the dimer interface of insulin. Semi-classical simulations of aromatic-aromatic interactions at this interface suggested that substitution of residue Tyr by Trp would preserve native structure while enhancing dimerization (and hence hexamer stability). The crystal structure of a [Trp]insulin analog (determined as a TR zinc hexamer at a resolution of 2.25 Å) was observed to be essentially identical to that of WT insulin. Remarkably and yet in general accordance with theoretical expectations, spectroscopic studies demonstrated a 150-fold increase in the lifetime of the variant hexamer, a critical pharmacokinetic parameter influencing design of long-acting formulations. Functional studies in diabetic rats indeed revealed prolonged action following subcutaneous injection. The potency of the Trp-modified analog was equal to or greater than an unmodified control. Thus, exploiting a general quantum-chemical feature of protein structure and stability, our results exemplify a mechanism-based approach to the optimization of a therapeutic protein assembly. PubMed: 29880646DOI: 10.1074/jbc.RA118.003650 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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