@article{ChenGehringerLorenz2018,
  author    = {Chen, Dan and Gehringer, Matthias and Lorenz, Sonja},
  title     = {Developing Small-Molecule Inhibitors of HECT-Type Ubiquitin Ligases for Therapeutic Applications: Challenges and Opportunities},
  series = {ChemBioChem},
  volume    = {19},
  journal   = {ChemBioChem},
  doi       = {10.1002/cbic.201800321},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222412},
  pages     = {2123-2135},
  year      = {2018},
  abstract  = {The ubiquitin system regulates countless physiological and disease-associated processes and has emerged as an attractive entryway for therapeutic efforts. With over 600 members in the human proteome, ubiquitin ligases are the most diverse class of ubiquitylation enzymes and pivotal in encoding specificity in ubiquitin signaling. Although considerable progress has been made in the identification of small molecules targeting RING ligases, relatively little is known about the "druggability" of HECT (homologous to E6AP C terminus) ligases, many of which are critically implicated in human pathologies. A major obstacle to optimizing the few available ligands is our incomplete understanding of their inhibitory mechanisms and the structural basis of catalysis in HECT ligases. Here, we survey recent approaches to manipulate the activities of HECT ligases with small molecules to showcase the particular challenges and opportunities these enzymes hold as therapeutic targets.},
  language  = {en}
}
@article{AkhoonSinghVarshneyetal.2014,
  author    = {Akhoon, Bashir A. and Singh, Krishna P. and Varshney, Megha and Gupta, Shishir K. and Shukla, Yogeshwar and Gupta, Shailendra K.},
  title     = {Understanding the Mechanism of Atovaquone Drug Resistance in Plasmodium falciparum Cytochrome b Mutation Y268S Using Computational Methods},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {10},
  doi       = {10.1371/journal.pone.0110041},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114882},
  pages     = {e110041},
  year      = {2014},
  abstract  = {The rapid appearance of resistant malarial parasites after introduction of atovaquone (ATQ) drug has prompted the search for new drugs as even single point mutations in the active site of Cytochrome b protein can rapidly render ATQ ineffective. The presence of Y268 mutations in the Cytochrome b (Cyt b) protein is previously suggested to be responsible for the ATQ resistance in Plasmodium falciparum (P. falciparum). In this study, we examined the resistance mechanism against ATQ in P. falciparum through computational methods. Here, we reported a reliable protein model of Cyt bc1 complex containing Cyt b and the Iron-Sulphur Protein (ISP) of P. falciparum using composite modeling method by combining threading, ab initio modeling and atomic-level structure refinement approaches. The molecular dynamics simulations suggest that Y268S mutation causes ATQ resistance by reducing hydrophobic interactions between Cyt bc1 protein complex and ATQ. Moreover, the important histidine contact of ATQ with the ISP chain is also lost due to Y268S mutation. We noticed the induced mutation alters the arrangement of active site residues in a fashion that enforces ATQ to find its new stable binding site far away from the wild-type binding pocket. The MM-PBSA calculations also shows that the binding affinity of ATQ with Cyt bc1 complex is enough to hold it at this new site that ultimately leads to the ATQ resistance.},
  language  = {en}
}
@article{ZukherNovikovaTikhonovetal.2014,
  author    = {Zukher, Inna and Novikova, Maria and Tikhonov, Anton and Nesterchuk, Mikhail V. and Osterman, Ilya A. and Djordjevic, Marko and Sergiev, Petr V. and Sharma, Cynthia M. and Severinov, Konstantin},
  title     = {Ribosome-controlled transcription termination is essential for the production of antibiotic microcin C},
  series = {Nucleic Acids Research},
  volume    = {42},
  journal   = {Nucleic Acids Research},
  number    = {19},
  issn      = {0305-1048},
  doi       = {10.1093/nar/gku880},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114839},
  pages     = {11891-11902},
  year      = {2014},
  abstract  = {Microcin C (McC) is a peptide-nucleotide antibiotic produced by Escherichia coli cells harboring a plasmid-borne operon mccABCDE. The heptapeptide MccA is converted into McC by adenylation catalyzed by the MccB enzyme. Since MccA is a substrate for MccB, a mechanism that regulates the MccA/MccB ratio likely exists. Here, we show that transcription from a promoter located upstream of mccA directs the synthesis of two transcripts: a short highly abundant transcript containing the mccA ORF and a longer minor transcript containing mccA and downstream ORFs. The short transcript is generated when RNA polymerase terminates transcription at an intrinsic terminator located in the intergenic region between the mccA and mccB genes. The function of this terminator is strongly attenuated by upstream mcc sequences. Attenuation is relieved and transcription termination is induced when ribosome binds to the mccA ORF. Ribosome binding also makes the mccA RNA exceptionally stable. Together, these two effects-ribosome induced transcription termination and stabilization of the message-account for very high abundance of the mccA transcript that is essential for McC production. The general scheme appears to be evolutionary conserved as ribosome-induced transcription termination also occurs in a homologous operon from Helicobacter pylori.},
  language  = {en}
}