Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P50583 (asymmetrical)
 12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

WIN 64821 (1) is a substance P (SP) antagonist isolated from a fungal culture (Aspergillus sp., SC319). It is a symmetrical dimer biosynthesized from four aromatic amino acid molecules: each equivalent half of the dimer is constructed from one molecule of phenylalanine (Phe) and one molecule of tryptophan (Trp). Feeding analogs of Phe, Trp, and other amino acids to intact cells of SC319 has yielded 36 biosynthetic analogs of WIN 64821. The analogs fall into three categories: substitutions on the indoline ring, substitutions on the Phe-derived phenyl ring, and replacement of the phenyl ring by an aliphatic group. In addition, these directed biosynthesis experiments generated asymmetrical dimers (derived from three amino acids) and, often, symmetrical dimers (derived from two amino acids). The relative SP binding affinities of several analogs suggest involvement of both the indoline and phenyl moieties in SP receptor binding.
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PMID:WIN 64821, a novel neurokinin antagonist produced by an Aspergillus sp. III. Biosynthetic analogs. 751 39

The plasma membrane dopamine transporter is located on presynaptic nerve terminals and is responsible for the termination of dopaminergic neurotransmission via dopamine reuptake. The dopamine transporter may also contribute to the pathogenesis of Parkinson disease. Dopamine transporter expression correlates well with susceptibility to neuronal degeneration in 1-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine (MPTP)-induced parkinsonism. Recent studies have implicated the dopamine transporter in the uptake of both this neurotoxin and its metabolite, MPP(+), as well as another experimental neurotoxin, 6-hydroxydopamine. In these studies we examined the role of the dopamine transporter in the neurotoxicity of both MPP(+) and 6-hydroxydopamine in the rat brain using in vivo administration of phosphorothioate antisense oligonucleotides targeting dopamine transporter mRNA. Infusion of dopamine transporter antisense (1 nmol/day, 7 days) into the left substantia nigra pars compacta resulted in reduced (3)H-WIN 35-428 binding in the left striatum and significant levodopa and amphetamine-induced contralateral rotations. Unilateral pretreatment with dopamine transporter antisense prior to bilateral intrastriatal infusion of either MPP(+) or 6-hydroxydopamine resulted in asymmetrical striatal (3)H-WIN 35-428 binding and dopamine content as well as significant apomorphine-induced ipsilateral rotations, suggesting neuroprotection of nigrostriatal neurons on the antisense-treated side. Thus, the dopamine transporter appears to play a critical role in determining susceptibility to the experimental neurotoxins MPP(+) and 6-hydroxydopamine. In light of this, the dopamine transporter may prove useful, both as a marker for susceptibility to Parkinson's disease and as a target for therapeutic intervention.
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PMID:Dopamine transporter function assessed by antisense knockdown in the rat: protection from dopamine neurotoxicity. 1088 Oct 39

The human rhinovirus 14 (HRV14) protomer, with or without the antiviral compound WIN 52084s, was simulated using molecular dynamics and rotational symmetry boundary conditions to model the effect of the entire icosahedral capsid. The protein asymmetrical unit, comprising four capsid proteins (VP1, VP2, VP3, and VP4) and two calcium ions, was solvated both on the exterior and the interior to fill the inside of the capsid. The stability of the simulations of this large system (~800 residues and 6,650 water molecules) is comparable to more conventional globular protein simulations. The influence of the antiviral compound on compressibility and positional fluctuations is reported. The compressibility, estimated from the density fluctuations in the region of the binding pocket, was found to be greater with WIN 52084s bound than without the drug, substantiating previous computations on reduced viral systems. An increase in compressibility correlates with an entropically more favorable system. In contrast to the increase in density fluctuations and compressibility, the positional fluctuations decreased dramatically for the external loops of VP1 and the N-terminus of VP3 when WIN 52084s is bound. Most of these VP1 and VP3 loops are found near the fivefold axis, a region whose mobility was not considered in reduced systems, but can be observed with this simulation of the full viral protomer. Altered loop flexibility is consistent with changes in proteolytic sensitivity observed experimentally. Moreover, decreased flexibility in these intraprotomeric loops is noteworthy since the externalization of VP4, part of VP1, and RNA during the uncoating process is thought to involve areas near the fivefold axis. Both the decrease in positional fluctuations at the fivefold axis and the increase in compressibility near the WIN pocket are discussed in relationship to the antiviral activity of stabilizing the virus against uncoating.
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PMID:Molecular dynamics simulations of human rhinovirus and an antiviral compound. 1115 87