Structure-Based Analysis of Single Nucleotide Variants in the Renin-Angiotensinogen Complex

Abstract

The Renin-Angiotensin System (RAS) plays an important role in regulating blood pressure and controlling sodium levels in the blood. Hyperactivity of this system has been linked to numerous conditions including hypertension, kidney disease, and congestive heart failure. As such, various classes of drugs have been developed to inhibit this system. These drugs are aimed at preventing angiotensin II from performing its function by inhibiting angiotensin II receptors or inhibiting angiotensin-converting enzyme from converting angiotensin I to angiotensin II. The last class of inhibitors is aimed at preventing angiotensin I from being formed by preventing renin from interacting with a plasma protein called angiotensinogen. In this study, we provide a structure-based analysis of the effect of single nucleotide variants on the interaction between renin and angiotensinogen with the aim of revealing important residues and potentially damaging variants.

Modulation of Human Hsp90α Conformational Dynamics by Allosteric Ligand Interaction at the C-Terminal Domain

“…The average reachability of a residue (L i ) is thus defined as the average number of steps required to reach residue i from any other residue in the network. The metric BC is related to L in that it is a measure of how often on average a residue is utilized in shortest path navigation and has been previously shown to be an effective measure for the identification of functional residues implicated in intra-protein communication37,48 , protein-ligand49 and protein-protein binding sites50,51 , as well as nonsynonymous SNP analysis52,53 . To evaluate the relative effect of CTD bound ligand on the connectivity of the protein we compare each proteinligand complex to the ligand-free ATP-only complex by monitoring the change in L i (ΔL i ) and BC (ΔBC) over the course of the MD trajectory.…”

HUMA: A platform for the analysis of genetic variation in humans

“…Nevertheless, HUMA can be searched from the angle of any of the four data types described previously. Previously, HUMA was used to study the effects of variation on the Renin‐Angiotensin System (RAS) (Brown, Sheik Amamuddy, & Tastan Bishop, ). To illustrate this functionality, we will now present a case study of how a user might go about analyzing the disease, “beta‐thalassemia” (MIM# 613985), via the HUMA Web interface.…”

Allosteric Modulation of Conformational Dynamics in Human Hsp90α: A Computational Study

“…BC is associated with L in that it is proportional to the number of shortest paths passing through a given residue, thus providing a measure of the usage frequency of a residue in cross network communication, where high usage residues are considered to potentially play a role in controlling intra-protein communication (Ozbaykal et al, 2015). The efficiency of this method for the calculation and analysis of BC and ΔL i along the MD simulation has previously been shown in a recent study on single nucleotide variants in the renin-angiotensinogen complex (Brown et al, 2017b). Here, we apply this analysis technique to each of the closed and FO complex configurations.…”

“…BC has been shown to be an effective measure for identifying functional residues implicated in the control of intra-protein communication (Ozbaykal et al, 2015;Brown et al, 2017b), as well as protein-ligand (Liu et al, 2011) and protein-protein binding sites (del Sol et al, 2005;Cheng et al, 2007) (see review (Taylor, 2013) for other examples). Here, BC is calculated for the closed and FO complexes to identify individual/groups of residues important for intra-and inter-protomer communication.…”