The crystal structure of human alpha1-tryptase reveals a blocked substrate-binding region

J Mol Biol. 2002 Aug 16;321(3):491-502. doi: 10.1016/s0022-2836(02)00625-3.


Human mast cell tryptases represent a subfamily of trypsin-like serine proteinases implicated in asthma. Unlike beta-tryptases, alpha-tryptases apparently are proteolytically inactive. We have solved the 2.2A crystal structure of mature human alpha1-tryptase. It reveals a frame-like tetrameric architecture that, surprisingly, does not require heparin-binding for stability. In marked contrast to beta2-tryptase, the Ser214-Gly219 segment, which normally provides the template for substrate binding, is kinked in alpha-tryptase, thereby blocking its non-primed subsites. This so far unobserved subsite distortion is incompatible with productive substrate binding and processing. alpha-Tryptase apparently is trapped in this off-conformation by repulsions and attractions of the Asp216 side-chain. However, proteolytic activity could be generated by an induced-fit mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Crystallography, X-Ray
  • Humans
  • Mast Cells / enzymology
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Conformation
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Serine Endopeptidases / chemistry*
  • Serine Endopeptidases / metabolism
  • Substrate Specificity
  • Tryptases


  • Recombinant Proteins
  • Serine Endopeptidases
  • Tryptases

Associated data

  • PDB/1LTO