Latrunculin A

Molecular Dynamics Simulation Reveal the Mechanism of Resistance of Mutant Actins to Latrunculin A - Insight into Specific Modifications to Design Novel Drugs to Overcome Resistance.[Pubmed:27484118]

Curr Comput Aided Drug Des. 2016;12(2):107-18.

BACKGROUND: Mutant actins D157E and R183A-D184A are reported to resist the anticancer drug Latrunculin A (LAT); though identified, the mechanism of resistance is not clearly understood. OBJECTIVE: To design better molecules that can overcome the resistance caused by mutations it is important to define precise pharmacophoric regions in LAT based on the mechanism of resistance on the mutant actin -LAT interactions. METHODS: To address this we have conducted 20 nano seconds (ns) simulation of mutant actins - LAT complex and compared it with the 20ns simulation of wild actin - LAT complex. Functions as the binding free energy, distance between LAT and binding site residues, LAT and actin domains, dihedral angle analysis, motional correlation were studied of these simulations. RESULTS: Grounded on these studies, four sites in LAT are identified to be crucial for modification. Bulkier ring moieties containing nitrogen in place of the double bonded oxygen in the macrocyclic lactone ring may be considered to establish interactions with Glu214. The nitrogen in 2-thiazolidinone moiety can be substituted with a hydrophobic ring to stabilise the interaction with the Asp157Glu and the oxygen in the cyclohexane of LAT with hydrophilic groups to strengthen their interaction with Tyr69. The nitrogen of the 2-thiazolidinone moiety can be replaced with nitrogen containing rings to improve inhibition of the actin polymerisation. Apart from this chemical groups on the sulphur of 2-thiazolidinone moiety to improve the hydrophobic interaction with actin is also identified for modification. CONCLUSION: Based on this a combinatorial library of 46 LAT analogs was generated and docked with the wild and mutant actins to identify potent leads to become anti-actin anticancer drugs.

Latrunculin A - Insight into Specific Modifications to Design Novel Drugs to Overcome Resistance.[Pubmed:27146706]

Curr Comput Aided Drug Des. 2016 May 5. pii: CAD-EPUB-75422.

Mutant actins D157E and R183A-D184A are reported to resist the anticancer drug Latrunculin A (LAT); though identified, the mechanism of resistance is not clearly understood. To design a better molecule that can overcome the resistance caused by mutations it is important to define precise pharmacophoric regions in LAT based on the mechanism of resistance on the mutant actin -LAT interactions. To address this we have conducted 20 nano seconds (ns) simulation of mutant actins - LAT complex and compared it with the 20ns simulation of wild actin - LAT complex. Functions as the binding free energy, distance between LAT and binding site residues, LAT and actin domains, dihedral angle analysis, motional correlation were studied for these simulations. Grounded on these observations and studies, four sites in LAT are identified to be crucial for modification. Bulkier ring moieties containing nitrogen in place of the double bonded oxygen in the macrocyclic lactone ring may be considered to establish interactions with Glu214. The nitrogen in 2-thiazolidinone moiety can be substituted with a hydrophobic ring to stabilize the interaction with the Asp157 which is mutated to Glu157and the oxygen in the cyclohexane of LAT with hydrophilic atoms or groups to strengthen their interaction with Tyr69. The nitrogen of the 2-thiazolidinone moiety can be replaced with aromatic nitrogen containing rings to improve inhibition of the actin polymerisation. Apart from this, chemical groups on the sulphur of 2-thiazolidinone moiety to improve the hydrophobic interaction with actin and saturating the double bonds between carbons 10 and 11 to control the conformational flexibility of the LAT are also identified for modification. Based on this a combinatorial library of 46 LAT analogs was generated and docked with the wild and mutant actins to identify potent leads to become anti-actin anticancer drugs.

Latrunculin A-Induced Perturbation of the Actin Cytoskeleton Mediates Pap1p-Dependent Induction of the Caf5p Efflux Pump in Schizosaccharomyces pombe.[Pubmed:28040778]

G3 (Bethesda). 2017 Feb 9;7(2):723-730.

As part of an earlier study aimed at uncovering gene products with roles in defending against Latrunculin A (LatA)-induced cytoskeletal perturbations, we identified three members of the oxidative stress response pathway: the Pap1p AP-1-like transcription factor, the Imp1p alpha-importin, and the Caf5p efflux pump. In this report, we characterize the pathway further and show that Pap1p translocates from the cytoplasm to the nucleus in an Imp1p-dependent manner upon LatA treatment. Moreover, preventing this translocation, through the addition of a nuclear export signal (NES), confers the same characteristic LatA-sensitive phenotype exhibited by pap1Delta cells. Lastly, we show that the caf5 gene is induced upon exposure to LatA and that Pap1p is required for this transcriptional upregulation. Importantly, the expression of trr1, a Pap1p target specifically induced in response to oxidative stress, is not significantly altered by LatA treatment. Taken together, these results suggest a model in which LatA-mediated cytoskeletal perturbations are sensed, triggering the Imp1p-dependent translocation of Pap1p to the nucleus and the induction of the caf5 gene (independently of oxidative stress).

A Genetic Screen for Fission Yeast Gene Deletion Mutants Exhibiting Hypersensitivity to Latrunculin A.[Pubmed:27466272]

G3 (Bethesda). 2016 Oct 13;6(10):3399-3408.

Fission yeast cells treated with low doses of the actin depolymerizing drug, Latrunculin A (LatA), delay entry into mitosis via a mechanism that is dependent on both the Clp1p and Rad24p proteins. During this delay, cells remain in a cytokinesis-competent state that is characterized by continuous repair and/or reestablishment of the actomyosin ring. In this manner, cells ensure the faithful completion of the preceding cytokinesis in response to perturbation of the cell division machinery. To uncover other genes with a role in this response, or simply genes with roles in adapting to LatA-induced stress, we carried out a genome-wide screen and identified a group of 38 gene deletion mutants that are hyper-sensitive to the drug. As expected, we found genes affecting cytokinesis and/or the actin cytoskeleton within this set (ain1, acp2, imp2). We also identified genes with roles in histone modification (tra1, ngg1), intracellular transport (apl5, aps3), and glucose-mediated signaling (git3, git5, git11, pka1, cgs2). Importantly, while the identified gene deletion mutants are prone to cytokinesis failure in the presence of LatA, they are nevertheless fully capable of cell division in the absence of the drug. These results indicate that fission yeast cells make use of a diverse set of regulatory modules to counter abnormal cytoskeletal perturbations, and furthermore, that these modules act redundantly to ensure cell survival and proliferation.

Actin-latrunculin A structure and function. Differential modulation of actin-binding protein function by latrunculin A.[Pubmed:10859320]

J Biol Chem. 2000 Sep 8;275(36):28120-7.

Latrunculin A is used extensively as an agent to sequester monomeric actin in living cells. We hypothesize that additional activities of Latrunculin A may be important for its biological activity. Our data are consistent with the formation of a 1:1 stoichiometric complex with an equilibrium dissociation constant of 0.2 to 0.4 micrometer and provide no evidence that the actin-Latrunculin A complex participates in the elongation of actin filaments. Profilin and Latrunculin A bind independently to actin, whereas binding of thymosin beta(4) to actin is inhibited by Latrunculin A. Potential implications of this differential effect on actin-binding proteins are discussed. From a structural perspective, if Latrunculin A binds to actin at a site that sterically influences binding by thymosin beta(4), then the observation that Latrunculin A inhibits nucleotide exchange on actin implies an allosteric effect on the nucleotide binding cleft. Alternatively, if, as previously postulated, Latrunculin A binds in the nucleotide cleft of actin, then its ability to inhibit binding by thymosin beta(4) is a surprising result that suggests that significant allosteric changes affect the thymosin beta(4) binding site. We show that Latrunculin A and actin form a crystalline structure with orthorhombic space group P2(1)2(1)2(1) and diffraction to 3.10 A. A high resolution structure with optimized crystallization conditions should provide insight regarding these remarkable allosteric properties.

Latrunculin A (LAT-A) is a toxin isolated from the red sea sponge Latrunculia magnifica, binds to actin monomers, inhibits polymerization of actin, with Kds of 0.1, 0.4, 4.7 μM and 0.19 μM for ATP-actin, ADP-Pi-actin, ADP-actin and G-actin, respectively.

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