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1.
Genet. mol. biol ; 32(3): 645-651, 2009. ilus, tab
Article in English | LILACS | ID: lil-522337

ABSTRACT

In this article, we describe a novel methodology to extract semantic characteristics from protein structures using linear algebra in order to compose structural signature vectors which may be used efficiently to compare and classify protein structures into fold families. These signatures are built from the pattern of hydrophobic intrachain interactions using Singular Value Decomposition (SVD) and Latent Semantic Indexing (LSI) techniques. Considering proteins as documents and contacts as terms, we have built a retrieval system which is able to find conserved contacts in samples of myoglobin fold family and to retrieve these proteins among proteins of varied folds with precision of up to 80 percent. The classifier is a web tool available at our laboratory website. Users can search for similar chains from a specific PDB, view and compare their contact maps and browse their structures using a JMol plug-in.


Subject(s)
Animals , Databases, Factual , Proteins/classification , Semantics , Mathematics
2.
Genet. mol. res. (Online) ; 3(4): 554-563, 2004. ilus, tab, graf
Article in English | LILACS | ID: lil-410899

ABSTRACT

Angiotensin I-converting enzyme (ACE) is a dipeptidyl-carboxypeptidase expressed in endothelial, epithelial and neuroepithelial cells. It is composed of two domains, known as N- and C-domains, and it is primarily involved in blood pressure regulation. Although the physiological functions of ACE are not limited to its cardiovascular role, it has been an attractive target for drug design due to its critical role in cardiovascular and renal disease. We examined natural structures based on bradykinin-potentiating peptides (BPPs) extracted from Bothrops jararaca venom for ACE inhibition. Modeling, docking and molecular dynamics were used to study the conserved residues in the S2’, S1’ and S1 positions that allow enzyme-substrate/inhibitor contacts. These positions are conserved in other oligopeptidases, and they form tight and non-specific contacts with lisinopril, enalapril and BPP9a inhibitors. The only specific inhibitor for human somatic ACE (sACE) was BPP9a, which is instable in the N-sACE-BPP9a complex due to repulsive electrostatic interactions between Arg P4-Arg 412 residues. Specificity for the C-terminal domain in human sACE inhibition was confirmed by electrostatic interaction with the Asp 1008 residue. Peptide-like BPP structures, naturally developed by snakes across millions of years of evolution, appear to be good candidates for the development of domain-selec tive ACE inhibitors with high stability and improved pharmacological profiles.


Subject(s)
Humans , Animals , Angiotensin-Converting Enzyme Inhibitors/chemistry , Antihypertensive Agents/chemistry , Bothrops , Bradykinin/chemistry , Crotalid Venoms/chemistry , Oligopeptides/pharmacology , Catalytic Domain , Drug Design , Drug Synergism , Models, Molecular , Oligopeptides/chemistry , Oligopeptides/isolation & purification , Substrate Specificity
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