title: Model of the TBP-TFIIB complex from Plasmodium falciparum: interface analysis and perspectives as a new target for antimalarial design.
abstract: BACKGROUND
  Malaria affects 200-300 million individuals per year worldwide. Plasmodium falciparum is the causative agent of the most severe and mortal type of malaria. The need for new antimalarials comes from the widespread resistance to those in current use. New antimalarial targets are required to increase chemical diversity and effectiveness of the drugs. The research for such new targets and drug chemotypes is aided by structure-based drug design. We present a model of the TBP-TFIIB complex from P. falciparum (pfTBP-pfTFIIB) and a detailed study of the interactions at the TBP-TFIIB interface.
  
  
  METHODS
  The model was built using standard methodology, optimized energetically and evaluated structurally. We carried out an analysis of the interface considering its evolution, available experimental data on TBP and TFIIB mutants, and the main conserved and non-conserved interactions. To support the perspective of using this complex as a new target for rational antimalarial design, we present the comparison of the pfTBP-pfTFIIB interface with its human homolog.
  
  
  RESULTS
  Despite the high residue conservation at the interface, we identified a potential region, composed of species-specific residues that can be used for rational antimalarial design.
  
  
  CONCLUSIONS
  Currently there are no antimalarial drugs targeted to stop the nuclear transcription process, a vital event for all replication stages of P. falciparum. Due to its absolute requirement in transcription initiation, we consider the pfTBP-pfTFIIB interface as a new potential target for novel antimalarial chemotypes.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad Autónoma del Estado de Morelos, Morelos, Mexico.
authors.forename: Jacob
authors.initials: J
authors.lastname: Buendía-Orozco
authors.forename: Adán
authors.initials: A
authors.lastname: Guerrero
authors.forename: Nina
authors.initials: N
authors.lastname: Pastor
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D018360:Crystallography, X-Ray; D019143:Evolution, Molecular; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D016366:Open Reading Frames; D010755:Organophosphates / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D035581:Transcription Factor TFIIB / Q000737:chemistry*; D014158:Transcription, Genetic
chemical_list: D000962:Antimalarials; D010755:Organophosphates; D035581:Transcription Factor TFIIB; C009524:tributyl phosphate