Publications by authors named "Alisha D Caliman"

Atypical protein kinase C (aPKC) isozymes are unique in the PKC superfamily in that they are not regulated by the lipid second messenger diacylglycerol, which has led to speculation about whether a different second messenger acutely controls their function. Here, using a genetically encoded reporter that we designed, aPKC-specific C kinase activity reporter (aCKAR), we found that the lipid mediator sphingosine 1-phosphate (S1P) promoted the cellular activity of aPKC. Intracellular S1P directly bound to the purified kinase domain of aPKC and relieved autoinhibitory constraints, thereby activating the kinase.

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Article Synopsis
  • The A adenosine receptor (A AR) is a G protein-coupled receptor linked to various diseases, including inflammation and cancer.
  • Recent molecular dynamics simulations identified four different conformers of the A AR: active, intermediate 1, intermediate 2, and inactive.
  • Using a mapping algorithm, five non-orthosteric sites for potential drug development were discovered, particularly in the active and inactive conformations, suggesting they could be targeted for new treatments.
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Activation of the first sphingosine-1-phosphate receptor (S1PR ) promotes permeability of the blood brain barrier, astrocyte and neuronal protection, and lymphocyte egress from secondary lymphoid tissues. Although an agonist often activates the S1PR , the receptor exhibits high levels of basal activity. In this study, we performed long-timescale molecular dynamics and accelerated molecular dynamics (aMD) simulations to investigate activation mechanisms of the ligand-free (apo) S1PR .

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G-protein-coupled receptors (GPCRs) are important membrane proteins that mediate cellular signaling and represent primary targets for about one-third of currently marketed drugs. Recent x-ray crystallographic studies identified distinct conformations of GPCRs in the active and inactive states. An allosteric sodium ion was found bound to a highly conserved D2.

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The activation/deactivation processes for G-protein coupled receptors (GPCRs) have been computationally studied for several different classes, including rhodopsin, the β2 adrenergic receptor, and the M2 muscarinic receptor. Despite determined cocrystal structures of the adenosine A2A receptor (A2A AR) in complex with antagonists, agonists and an antibody, the deactivation process of this GPCR is not completely understood. In this study, we investigate the convergence of two apo simulations, one starting with an agonist-bound conformation (PDB: 3QAK)(14) and the other starting with an antagonist-bound conformation (PDB: 3EML)(11) .

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