Inhibition of carboxypeptidase A by excess zinc: Analysis of the structural determinants by X-ray crystallography

Mariola Gomez-Ortiz, Francesc X. Gomis-Rüth, Robert Huber, Francesc X. Avilés

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69 Citations (Scopus)

Abstract

Pancreatic metallocarboxypeptidases are inhibited by a millimolar excess of zinc together with other exo- and endometalloproteases. We have analyzed the structure of bovine carboxypeptidase A inhibited by an excess of zinc ions using X-ray crystallography at 1.7 Å overall resolution. Under these conditions, a second zinc is observed to bind to the enzyme active site, establishing a distorted tetrahedrally coordinated complex which involves Glu-270 (the general base for catalysis), a water molecule, a chloride ion, and a hydroxide ion. This hydroxide ion forms a 114°angular bridge between the inhibitory and the catalytic zinc ions, which are at a distance of 3.3 Å from one another. The inhibitory zinc holds the hydroxide at nearly the same location as a previously observed active site water molecule (W571) and probably perturbs the substrate positioning and stereochemical rearrangements required for substrate cleavage during catalysis.
Original languageEnglish
Pages (from-to)336-340
JournalFEBS Letters
Volume400
DOIs
Publication statusPublished - 6 Jan 1997

Keywords

  • Carboxypeptidase A
  • Enzyme inhibition
  • Metalloenzyme
  • X-ray crystallography
  • Zinc inhibition

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