PDBsum entry 6tyh

Hormone

PDB id: 6tyh

Contents

Protein chains

(+ 0 more) 22 a.a.

28 a.a.

29 a.a.

Ligands

IPH ×7

ACN ×2

GOL ×2

Metals

_CL ×2

_ZN ×2

Waters ×231

References listed in PDB file

Key reference

• Title: Novel four-Disulfide insulin analog with high aggregation stability and potency.
• Authors: X.Xiong, A.Blakely, P.Karra, M.A.Vandenberg, G.Ghabash, F.Whitby, Y.W.Zhang, M.J.Webber, W.L.Holland, C.P.Hill, D.H.Chou.
• Ref.: Chem Sci, 2020, 11, 195-200. [DOI no: 10.1039/c9sc04555d]
• PubMed id: 32110371

Abstract

Although insulin was first purified and used therapeutically almost a century ago, there is still a need to improve therapeutic efficacy and patient convenience. A key challenge is the requirement for refrigeration to avoid inactivation of insulin by aggregation/fibrillation. Here, in an effort to mitigate this problem, we introduced a 4^th disulfide bond between a C-terminal extended insulin A chain and residues near the C-terminus of the B chain. Insulin activity was retained by an analog with an additional disulfide bond between residues A22 and B22, while other linkages tested resulted in much reduced potency. Furthermore, the A22-B22 analog maintains the native insulin tertiary structure as demonstrated by X-ray crystal structure determination. We further demonstrate that this four-disulfide analog has similar in vivo potency in mice compared to native insulin and demonstrates higher aggregation stability. In conclusion, we have discovered a novel four-disulfide insulin analog with high aggregation stability and potency.