title: Rational redesign of inhibitors of furin/kexin processing proteases by electrostatic mutations.
abstract: OBJECTIVE
  To model the three-dimensional structure and investigate the interaction mechanism of the proprotein convertase furin/kexin and their inhibitors (eglin c mutants).
  
  
  METHODS
  The three-dimensional complex structures of furin/kexin with its inhibitors, eglin c mutants, were generated by modeller program using the newly published X-ray crystallographical structures of mouse furin and yeast kexin as templates. The electrostatic interaction energy of each complex was calculated and the results were compared with the experimentally determined inhibition constants to find the correlation between them.
  
  
  RESULTS
  High quality models of furin/kexin-eglin c mutants were obtained and used for calculation of the electrostatic interaction energies between the proteases and their inhibitors. The calculated electrostatic energies of interaction showed a linear correlation to the experimental inhibition constants.
  
  
  CONCLUSIONS
  The modeled structures give good explanations of the specificity of eglin c mutants to furin/kexin. The electrostatic interactions play important roles in inhibitory activity of eglin c mutants to furin/kexin. The results presented here provided quantitative structural and functional information concerning the role of the charge-charge interactions in the binding of furin/kexin and their inhibitors.
authors.affiliation: Key Laboratory of Proteomics, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiao-hui
authors.initials: XH
authors.lastname: Cai
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Da-fu
authors.initials: DF
authors.lastname: Ding
mesh_terms: D000818:Animals; D015195:Drug Design; D004347:Drug Interactions; D045683:Furin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D011506:Proteins; D015843:Serpins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D055672:Static Electricity
chemical_list: D011506:Proteins; D015843:Serpins; C028656:eglin proteinase inhibitors; D045683:Furin