ABSTRACT
The recent finding of a specific receptor for prorrenin/renin (PRR) has brought new insights into the physiology of the renin-angiotensin-aldosterone system. No undoubtable role has been described for this receptor so far. Its role seems to be important in chronic illnesses such as hypertension, possibly participating in the cardiovascular remodeling process, and diabetes where participation in inflammation development has been described. It is not possible, however, to explore the PRR function using classical pharmacological approaches due to the lack of specific agonists or antagonists. Two synthetic peptides have been described to accomplish these roles, but no conclusive data have been provided. There are no X-ray crystallography studies available to describe the structure and potential sites for drug development. So, the aim of this work was to model and theoretically describe the PRR. We describe and characterize the whole receptor protein, its spatial conformation and the potential interactions of PRR with the synthetic peptides available, describing the amino acid residues responsible for these interactions. This information provides the basis for directed development of drugs, seeking to agonize or antagonize PRR activity and study its function in health and ill stages.
Subject(s)
Molecular Dynamics Simulation , Protein Conformation , Receptors, Cell Surface/chemistry , Renin/chemistry , Vacuolar Proton-Translocating ATPases/chemistry , Amino Acid Sequence , Binding Sites , Catalytic Domain , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Sequence Data , Protein Binding , Protein Interaction Domains and Motifs , Receptors, Cell Surface/metabolism , Renin/metabolism , Sequence Alignment , Vacuolar Proton-Translocating ATPases/metabolismABSTRACT
Following the influenza A (H1N1) pandemic in Mexico and around the world in 2009, the numbers of oseltamivir-resistant clinical cases have increased through a mechanism that remains unclear. In this work, we focus on studying the mutated NA structures ADA71175 (GenBank) and 3CKZ (PDB ID). Recently crystallized NA (PDB ID: 3NSS) was used as a wild-type structure and template to construct the three-dimensional (3D) structure of ADA71175. Then, the NA mutants and 3NSS natives as well as their refined monomer structures as determined through MD simulations (snapshots at 50 ns) were used as models to perform a docking study using a set of aryl-oseltamivir derivatives. These aryl-oseltamivir derivatives have better recognition properties than oseltamivir because of cation-π interactions with a cluster of Arg residues (118, 292, and 371) at the binding site. This cluster of Arg residues represents a potential binding site for aryl-oseltamivir derivatives that are potentially new NA inhibitors.
