Molecular structure of leucine aminopeptidase at 2.7-Å resolution

Stephen K. Burley, Peter R. David, Allen Taylor, William N. Lipscomb

Research output: Contribution to journalArticlepeer-review

222 Scopus citations


The three-dimensional structure of bovine lens leucine aminopeptidase (EC complexed with bestatin, a slow-binding inhibitor, has been solved to 3.0-Å resolution by the multiple isomorphous replacement method with phase combination and density modification. In addition, the structure of the isomorphous native enzyme has been refined at 2.7-Å resolution, and the current crystallographic R factor is 0.169 for a model that includes the two zinc ions and all 487 amino acid residues comprising the asymmetric unit. The enzyme is physiologically active as a hexamer, which has 32 symmetry and is triangular in shape with a triangle edge length of 115 Å and maximal thickness of 90 Å. The monomers are crystallographically equivalent and each is folded into two unequal α/β domains connected by an α-helix to give a comma-like shape with approximate maximal dimensions of 90 × 55 × 55 Å3. The secondary structural composition is 40% α-helix and 19% β-strand. The N-terminal domain (160 amino acids) mediates trimer-trimer interactions and does not appear to participate directly in catalysis. The C-terminal domain (327 amino acids) is responsible for catalysis and binds the two zinc ions, which are 2.88 Å apart. The pair of metal ions is located near the edge of an eight-stranded, saddle-shaped β-sheet. One zinc ion is coordinated by carboxylate oxygen atoms of Asp-255, Asp-332, and Glu-334 and the carbonyl oxygen of Asp-332. The other zinc ion is coordinated by the carboxylate oxygen atoms of Asp-255, Asp-273, and Glu-334. The active site also contains two positively charged residues, Lys-250 and Arg-336. The six active sites are themselves located in the interior of the hexamer, where they line a disk-shaped cavity of radius 15 Å and thickness 10 Å. Access to this cavity is provided by solvent channels that run along the twofold symmetry axes.

Original languageEnglish (US)
Pages (from-to)6878-6882
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
StatePublished - Sep 1990
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General


  • Bestatin
  • Exopeptidase
  • X-ray crystallography
  • Zinc enzyme


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