Crystal structure of avian carboxypeptidase D domain II: A prototype for the regulatory metallocarboxypeptidase subfamily

F. X. Gomis-Rüth, V. Companys, Y. Qian, L. D. Fricker, J. Vendrell, F. X. Avilés, M. Coll

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Abstract

The crystal structure of domain II of duck carboxypeptidase D, a prohormone/propeptide processing enzyme integrated in a three repeat tandem in the natural system, has been solved, constituting a prototype for members of the regulatory metallocarboxypeptidase subfamily. It displays a 300 residue N-terminal α/β-hydrolase subdomain with overall topological similarity to and general coincidence of the key catalytic residues with the archetypal pancreatic carboxypeptidase A. However, numerous significant insertions/deletions in segments forming the funnel-like access to the active site explain differences in specificity towards larger protein substrates or inhibitors. This α/β-hydrolase subdomain is followed by a C-terminal 80 residue β-sandwich subdomain, unique for these regulatory metalloenzymes and topologically related to transthyretin and sugar-binding proteins. The structure described here establishes the fundamentals for a better understanding of the mechanism ruling events such as prohormone processing and will enable modelling of regulatory carboxypeptidases as well as a more rational design of inhibitors of carboxypeptidase D.

Original languageEnglish (US)
Pages (from-to)5817-5826
Number of pages10
JournalEMBO Journal
Volume18
Issue number21
DOIs
Publication statusPublished - Nov 1 1999

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Keywords

  • Carboxypeptidase
  • Inhibitor design
  • Metalloprotease
  • Transthyretin
  • X-ray crystal structure

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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