title: Analysis of the structure of calpain-10 and its interaction with the protease inhibitor SNJ-1715.
abstract: Calpain-10 (CAPN10) is a cysteine protease that is activated by intracellular calcium (Ca(2+)) and known to be involved in diseases such as cancer, heart attack, and stroke. A role for the CAPN10 gene in diabetes mellitus type II was recently identified. Hyper activation of the enzyme initiates a series of destructive cycles that can cause irreversible damage to cells. The development of inhibitors may be useful as therapeutic agents for a number of calpainopathies. In this paper, we have used the homology modelling technique to determine the 3D structure of calpain-10 from Homo sapiens. The model of calpain-10 obtained by homology modelling suggests that its active site is conserved among family members and the main interactions are similar to those observed for μ-calpain. Structural analysis revealed that there are small differences in the charge distribution and molecular surface of the enzyme. These differences are probably less dependent on calcium for calpain-10 than they are for μ-calpain. In addition, the ion pair Cys(-)/His(+) formation was observed using of Molecular Dynamics (MD) simulations that were based upon hybrid quantum mechanical/molecular mechanical (QM/MM) approaches. Finally, the binding of the SNJ-1715 inhibitor to calpain-10 was investigated in order to further understand the mechanism of inhibition of calpain-10 by this inhibitor at the molecular level.
authors.affiliation: Laboratório de Planejamento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CEP 66075-110 Belém, PA, Brazil; Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Pará, CEP 66075-110 Belém, PA, Brazil.
authors.forename: Ronaldo Correia
authors.initials: RC
authors.lastname: da Silva
authors.forename: Nelson Alberto N
authors.initials: NA
authors.lastname: de Alencar
authors.forename: Cláudio Nahum
authors.initials: CN
authors.lastname: Alves
authors.forename: Jerônimo
authors.initials: J
authors.lastname: Lameira
mesh_terms: D000595:Amino Acid Sequence; D002154:Calpain / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D015203:Reproducibility of Results; D016415:Sequence Alignment; D055672:Static Electricity; D013890:Thiourea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: C512439:SNJ 1715; D002154:Calpain; C415197:calpain 10; D013890:Thiourea
keywords: Calpain-10; Homology modelling; Inhibitor; MD; QM/MM