Mutation in angiotensin II type 1 receptor disrupts its binding to angiotensin II leading to hypotension: An insight into hydrogen bonding patterns

Abstract

To understand the role of angiotensin II type 1 receptor gene (AGTR1) gene products in relation to hypotension we have analyzed the single nucleotide polymorphisms (SNPs) associated with this gene. This can help us to understand the genetic variations that can alter the function of the gene products. In this present study, we report the polymorphic variant associated with AGTR1 and its weak interaction with angiotensin II (AngII) which leads to hypotension. Out of 1318 SNPs, six are found to be non-synonymous, of which rs1064533 shows significant damaging effect. A missense mutation (T1255G), i.e., from thymine to guanine for rs1064533 in AGTR1 gene results in amino acid substitution from cysteine (Cys) to tryptophan (Trp) in the receptor protein. A strong hydrogen bond exists between Cys289 of native AGTR1 protein and glutamine 167 of AngII. Interestingly, it is replaced by a weak hydrogen bond in the mutant protein between Trp289 (mutant residue) and serine 340. Such a substitution from small, hydrophilic to bulky, hydrophobic residue in AGTR1 protein results in reduced binding affinity of the receptor protein with AngII, leading to hypotension. The results presented from this in silico study will open up new prospect for genetic analysis of AGTR1 gene and will be beneficial to the researchers for understanding the role played by AGTR1 gene in hypotension disease.

Keywords

AGTR1 / AngII / hypotension / rs1064533 / cysteine / tryptophan

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Acknowledgement

Dr. Anand Anbarasu gratefully acknowledges the Indian council of Medical Research (ICMR), Government of India Agency for the research grant. We would like to thank the management of VIT for providing us the necessary funds and infrastructure for conducting this project.

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2014 Higher Education Press and Springer-Verlag Berlin Heidelberg