RESUMEN
Protein kinase C (PKC) comprises a family of ubiquitous enzymes transducing signals by the lipophilic second messenger sn-1, 2-diacylglycerol (DAG). Teleocidin and its structurally simpler congener indolactam-V (ILV) bind to PKC with high affinity. In this paper, we report our computational docking studies on ILV binding to PKC using an automatic docking computer program, MCDOCK. In addition, we used site-directed mutagenesis to assess the quantitative contribution of crucial residues around the binding site of PKC to the binding affinity of ILV to PKC. On the basis of the docking studies, ILV binds to PKC in its cis-twist conformation and forms a number of optimal hydrogen bond interactions. In addition, the hydrophobic groups in ILV form "specific" hydrophobic interactions with side chains of a number of conserved hydrophobic residues in PKC. The predicted binding mode for ILV is entirely consistent with known structure-activity relationships and with our mutational analysis. Our mutational analysis establishes the quantitative contributions of a number of conserved residues to the binding of PKC to ILV. Taken together, our computational docking simulations and analysis by site-directed mutagenesis provide a clear understanding of the interaction between ILV and PKC and the structural basis for design of novel, high-affinity, and isozyme-selective PKC ligands.
Asunto(s)
Indoles/química , Lactamas/química , Proteína Quinasa C/genética , Animales , Sitios de Unión/genética , Simulación por Computador , Diseño de Fármacos , Enlace de Hidrógeno , Toxinas de Lyngbya/química , Modelos Moleculares , Conformación Molecular , Mutagénesis Sitio-Dirigida , Ésteres del Forbol/química , Unión Proteica , Proteína Quinasa C/química , Proteína Quinasa C/metabolismo , Relación Estructura-ActividadRESUMEN
Data on malaria incidence and prevalence as well as on abundance of anopheline species collected in Jairampur, Arunachal Pradesh, show that P. falciparum contributed 27.59% of the total positive cases, most of these being recorded during July to September. Of the twelve anopheline species recorded, Anopheles maculatus was the most predominant comprising 54.32% of the total collection. Other common species were An. peditaeniatus, An. philippinensis and An. kochi in order of decreasing proportion. An. dirus, the known vector, was collected in the whole-night human bait catches (indoor) but in low numbers. An. philippinensis is implicated as another potential vector, and changes in anopheline/vector fauna are attributed to ecological succession.
Asunto(s)
Anopheles , Insectos Vectores , Malaria/epidemiología , Animales , Conducta Alimentaria , Humanos , Incidencia , India/epidemiología , Malaria/transmisión , Malaria Falciparum/epidemiología , Malaria Falciparum/transmisión , Plasmodium , Estaciones del AñoRESUMEN
A retrospective study was carried out on 119 Caucasians who were admitted to the Hospital for Tropical Diseases, London, for investigation of eosinophilia on return from the tropics. In 46 patients (38.7%) a definite parasitological diagnosis was made, and in all those followed up eosinophilia decreased with appropriate chemotherapy. In those patients where no cause for eosinophilia could be found, results suggest that empirical treatment with a broad spectrum anthelmintic agent may be justified in an attempt to produce a normal blood picture.