Abstract
AbstractThe treatment of insulin-dependent diabetes mellitus is characterized by artificial supplementation of pancreatic β-cell ability to regulate sugar levels in the blood. Even though various insulin analogs are crucial for reasonable glycemic control, understanding the dynamic mechanism of the insulin analogs may help to improve the best-protracted insulin analog to assist people with Type 1 Diabetes (T1D) to live comfortably while maintaining tight glycemic control. Here we present the high-resolution crystal structure of NN304, known as insulin detemir, to 1.7 Å resolution at cryogenic temperature. We computationally further investigated our crystal structure’s monomeric-dimeric conformation and dynamic profile by comparing it with a previously available detemir structure (PDB ID: 1XDA). Our structure (PDB ID: 8HGZ) obtained at elevated pH provides electrostatically triggered minor movements in the equilibrium between alternate conformational substates compared to the previous structure, suggesting it might induce an intermediate state in the dissociation pathway of the insulin detemir’s hexamer:dihexamer equilibrium. Supplemented with orientational cross-correlation analysis by Gaussian Network Model (GNM), this alternate oligomeric conformation offers the distinct cooperative motions originated by loose coupling of distant conformational substates of a protracted insulin analog that has not been previously observed.
Publisher
Cold Spring Harbor Laboratory
Reference35 articles.
1. Home PD. Plasma insulin profiles after subcutaneous injection: How close can we get to physiology in people with diabetes? Diabetes, Obes. Metab. 2015.
2. Ismail-Beigi F , Moghissi E , Tiktin M , Hirsch B , Inzucchi SE , Genuth S. Individualizing glycemic targets in type 2 diabetes mellitus: Implications of recent clinical trials. Ann Intern Med. 2011;
3. Donner T , Sarkar S. Insulin – Pharmacology, Therapeutic Regimens And Principles Of Intensive Insulin Therapy. Endotext. 2019.
4. Owens DR , Zinman B , Bolli GB. Insulins today and beyond. Lancet. 2001.