A computational structural biology study to understand the impact of mutation on structure–function relationship of inward-rectifier potassium ion channel Kir6.2 in human

Abstract

Type 2 diabetes (T2D) is clinically characterized via hyperglycemia. Polymorphism rs5219 in the KCNJ11 gene is a risk factor for developing T2D in humans. KCNJ11 encodes the ‘inward-rectifier potassium ion channel (Kir6.2)’. However, because of the absence of the complete crystal/NMR structures of Kir6.2 proteins, insight into its structure and function and its interaction with diverse ligands remain elusive to date. Therefore, a computational approach was employed for predicting the best plausible ‘three-dimensional’ structure of Kir6.2 as well as for studying the influence of mutation (p. GLU23LYS) on both architectures as well as the function of Kir6.2 employing simulation studies. Results obtained revealed that though, with increased time, ‘Gibbs free energy’ becomes positive, residues in wild type Kir6.2 experiences less random movement as compared to mutant Kir6.2. The less random movement of residues in wild type Kir6.2 represents the standard coupling between open and closing of ‘K_ATP channel’ and thus the normal secretion of insulin. The more dispersed motion of mutant Kir6.2 residues represents ‘overactivity’ of the ‘K_ATP channel’ and thus insulin ‘under-secretion’. Further, molecular docking and simulation studies identified two phytochemicals/drugs, namely, A-348441 and chushizisin I, which retains the wild type property of Kir6.2 after binding with mutant protein. Unlike A-348441, this is for the first time, the present study is reporting about the plausible anti-diabetic property of chushizisin I. As these two phytochemicals/drugs, namely, A-348441 and chushizisin I, have passed ADMET test, in the near future, they may be utilized as anti-diabetic drugs after further investigation.

Communicated by Ramaswamy H. Sarma

Keywords:

• KCNJ11
• Kir6.2
• mutation
• docking
• modelling
• molecular dynamics
• human
• drug
• phytochemical

Acknowledgement

We thank Dr. Julien Y. Dutheil and the Max Planck Institute for Evolutionary Biology, Plön, Germany, for providing the computational facility.

Disclosure statement

No potential conflict of interest was reported by the authors.