%0 Journal Article
%A Mesterházy, Edit
%A Lebrun, Colette
%A Jancsó, Attila
%A Delangle, Pascale
%D 2018
%T A Constrained Tetrapeptide as a Model of Cu(I) Binding
Sites Involving Cu4S6 Clusters in Proteins
%U https://acs.figshare.com/articles/journal_contribution/A_Constrained_Tetrapeptide_as_a_Model_of_Cu_I_Binding_Sites_Involving_Cu_sub_4_sub_S_sub_6_sub_Clusters_in_Proteins/5783220
%R 10.1021/acs.inorgchem.7b02735.s001
%2 https://acs.figshare.com/ndownloader/files/10206087
%K NMR spectroscopies
%K amide protons
%K Cu 4 S 6 core
%K peptide CdPPC
%K polymetallic species
%K ESI-MS
%K Cu 4 S 6 Clusters
%K Proteins Peptide design
%K Ac-Cys-Pro-Gly-Cys-NH 2
%K 1 H NMR
%K liver cells
%K peptide CPGC
%K metal binding sites
%K tetrapeptide CdPPC
%K UV
%K 10 17.5
%K solvent-shielded intramolecular hydrogen bond
%K Constrained Tetrapeptide
%K temperature coefficients
%K tetrapeptides Ac-Cys-dPro-Pro-Cys-NH 2
%K Cu overload
%K peptide backbone structure
%K diffusion-ordered NMR spectroscopy
%K Cu 4 L 3
%K metal-binding side chains
%K Cu homeostasis
%K electrospray ionization mass spectrometry
%K 1 order
%X Peptide
design is an efficient strategy to create relevant models of natural
metal binding sites found in proteins. The two short tetrapeptides
Ac-Cys-dPro-Pro-Cys-NH2 (CdPPC) and Ac-Cys-Pro-Gly-Cys-NH2 (CPGC) were synthesized and studied as mimics of Cu(I) binding
sites involved in Cu homeostasis. Both sequences contain β turn
inducing motifs to rigidify the peptide backbone structure and thereby
preorganize the metal-binding side chains. The more constrained structure
of the peptide CdPPC with respect to CPGC was evidenced by
the measurements of the temperature coefficients of the amide protons
by 1H NMR, which suggest a solvent-shielded intramolecular
hydrogen bond in CdPPC, and no H-bond in CPGC. The Cu(I)
complexes were studied by UV, circular dichroism (CD), and NMR spectroscopies
as well as electrospray ionization mass spectrometry (ESI-MS) experiments
in aqueous solution at physiological pH. The complexes formed with
CPGC showed a complicated speciation with the possible formation of
many polymetallic species. By contrast, the better preorganization
in CdPPC leads to the formation of a unique Cu4L3 complex involving a Cu4S6 core.
The formation of this specific cluster was confirmed by ESI-MS and
by diffusion-ordered NMR spectroscopy in solution. The affinity of
CdPPC for Cu(I) (β11pH7.4 = 1017.5 calculated for a CuL complex) is more than 1 order of
magnitude larger than the affinity measured for the less constrained
peptide CPGC. Besides, this stability constant value is very similar
to those reported with proteins. Therefore, the Cu(I) complex formed
with the simple tetrapeptide CdPPC in water at physiological
pH represents a very good model of Cu(I)-thiolate clusters found in
proteins. The extremely large selectivity (1011) in favor
of Cu(I) with respect to Zn(II), an abundant competitor in cells,
makes it a promising candidate to be targeted to the liver cells for
the localized treatment of Cu overload in Wilson’s disease.
%I ACS Publications