A minimalist chemical model of matrix metalloproteinases - Can small peptides mimic the more rigid metal binding sites of proteins?

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Abstract

In order tomimic the active center of matrix metalloproteinases (MMPs), we synthesized a pentadecapeptide (Ac-KAHEFGHSLGLDHSK-NH2) corresponding to the catalytic zinc(II) binding site of human MMP-13. The multi-domain structural organization of MMPs fundamentally determines their metal binding affinity, catalytic activity and selectivity. Our potentiometric, UV-visible, CD, EPR, NMR, mass spectrometric and kinetic studies are aimed to explore the usefulness of such flexible peptides to mimic the more rigid metal binding sites of proteins, to examine the intrinsic metal binding properties of this naked sequence, as well as to contribute to the development of a minimalist, peptide-based chemical model of MMPs, including the catalytic properties. Since the multiimidazole environment is also characteristic for copper(II), and recently copper(II) containing variants of MMPs have been identified, we also studied the copper(II) complexes of the above peptide. Around pH 6-7 the peptide, similarly to MMPs, offers a {3Nim} coordination binding site for both zinc(II) and copper(II). In the case of copper(II), the formation of amide coordinated species at higher pH abolished the analogy with the copper(II) containing MMP variant. On the other hand, the zinc(II)-peptide system mimics some basic features of the MMP active sites: the main species around pH 7 (ZnH2L) possesses a {3Nim,H2O} coordination environment, the deprotonation of the zinc-bound water takes place near the physiological pH, it forms relatively stable ternary complexes with hydroxamic acids, and the species ZnH2 L(OH) and ZnH2L(OH) 2 have notable hydrolytic activity between pH 7 and 9.

Original languageEnglish
Pages (from-to)61-69
Number of pages9
JournalJournal of Inorganic Biochemistry
Volume126
DOIs
Publication statusPublished - Jan 1 2013

Keywords

  • Copper(II)
  • Enzyme mimicking
  • Matrix metalloproteinase
  • Peptide
  • Zinc(II)

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry

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