6TYH

Four-Disulfide Insulin Analog A22/B22

Summary for 6TYH

• Entry DOI: 10.2210/pdb6tyh/pdb
• Descriptor: Insulin A chain, Insulin B chain, PHENOL, ... (8 entities in total)
• Functional Keywords: signalling, metabolism, hormone
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 12
• Total formula weight: 36361.31

Authors

Blakely, A.D.,Xiong, X. (deposition date: 2019-08-08, release date: 2019-11-13, Last modification date: 2024-10-30)

Primary citation

Xiong, X.,Blakely, A.,Karra, P.,VandenBerg, M.A.,Ghabash, G.,Whitby, F.,Zhang, Y.W.,Webber, M.J.,Holland, W.L.,Hill, C.P.,Chou, D.H.
Novel four-disulfide insulin analog with high aggregation stability and potency.
Chem Sci, 11:195-200, 2020

PubMed 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 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 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.

PubMed: 32110371
DOI: 10.1039/c9sc04555d

Experimental method

X-RAY DIFFRACTION (1.60001899481 Å)