It isn't natural: TRI peptides can selectively control the coordination number of a metal center by changing only one of the amino acids in the primary sequence. Replacement of the cysteine residue with penicillamine leads to a three‐coordinate complex CdIIS3, whereas substitution of alanine for leucine gives four‐coordinate CdS3O (see scheme).
Keywordscadmium; coordination modes; de novo peptides; metalloproteins; protein design One of the most important chemical concepts is defining how one molecule recognizes and controls the properties of another molecule or ion. Nowhere is this issue more significant than in the field of biomolecular recognition. Metalloproteins efficiently control the geometry and coordination number of metal ions as well as the types of ligands bound to them. Incorporation of metals in the correct binding site is essential for proper biological activity of the protein, regardless of whether the function is catalytic, structural, or regulatory. Despite the importance of metalloproteins, the major factors determining metalion selectivity and specificity are not yet well understood. Recent studies on metalloregulatory proteins and carbonic anhydrase suggest that coordination number and geometry of the metal ion are key elements. [1,2] This control becomes even more significant when proteins can bind two metal ions with different coordination environments. This is the case for the enzyme 5′-aminolevulinic acid dehydratase, which contains two Zn II centers, one bound in a five-coordinate geometry and the other bound in a pseudotetrahedral geometry. Interestingly, lead toxicity is mainly due to the replacement by a Pb II ion of the Zn II ion bound to the tetrahedral site. [3,4] Thus, a deep knowledge of the factors determining this delicate ion recognition is crucial to understanding the principles that govern metalloprotein structure and function.Using the de novo designed TRI peptide family (TRI = Ac-G-(LKALEEK) 4 -G-NH 2 ), we have been investigating the influence of protein environment on metal-ion specificity and Correspondence to: Vincent L. Pecoraro. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript how subtle changes in the amino acid sequence can fully control the coordination number of the metal ion. By exploiting our previous observations that we could influence the metal binding affinity in the TRI coiled coils by placing cysteine in either position a or d of the heptad repeat unit, we designed a TRI derivative with two cysteine binding sites (TRI L9CL19C, Table 1) that shows sequential and selective binding of Cd II ions, first to the a site and then to the d site. [5] This result highlights how site-specific binding of Cd II ions can be achieved in a de novo designed peptide containing two binding sites that are defined by the same first-coordination-sphere ligands, three cysteine residues in both cases, solely by changing the conformation and environment of the metal-binding cavity. Later, using the a binding sites, we designed two peptides, TRI L16Pen and TRI L12AL16C (Table 1), that are able to bind Cd II ions exclusively in a trigonal-planar structure and a pseudotetrahedral geometry, respectively. This precise control of the coordination number and geometry of the Cd II centers was achieved by controlling the steric constraints in the metal-binding pocket. [6] We know that thes...
Wie unnatürlich: Peptide der TRI‐Familie können durch Austausch nur eines Aminosäurerestes in der Primärsequenz die Koordinationszahl eines Metallzentrums kontrollieren. Der Ersatz eines Cysteinrestes durch Penicillamin führt zu dreifach koordinierten CdIIS3‐Komplexen, während bei Alanin‐Substitution eines Leucinrestes vierfach koordiniertes CdIIS3O resultiert (siehe Schema).
One of the most important chemical concepts is defining how one molecule recognizes and controls the properties of another molecule or ion. Nowhere is this issue more significant than in the field of biomolecular recognition. Metalloproteins efficiently control the geometry and coordination number of metal ions as well as the types of ligands bound to them. Incorporation of metals in the correct binding site is essential for proper biological activity of the protein, regardless of whether the function is catalytic, structural, or regulatory. Despite the importance of metalloproteins, the major factors determining metal-ion selectivity and specificity are not yet well understood. Recent studies on metalloregulatory proteins and carbonic anhydrase suggest that coordination number and geometry of the metal ion are key elements. [1,2] This control becomes even more significant when proteins can bind two metal ions with different coordination environments. This is the case for the enzyme 5'-aminolevulinic acid dehydratase, which contains two Zn II centers, one bound in a five-coordinate geometry and the other bound in a pseudotetrahedral geometry. Interestingly, lead toxicity is mainly due to the replacement by a Pb II ion of the Zn II ion bound to the tetrahedral site. [3,4] Thus, a deep knowledge of the factors determining this delicate ion recognition is crucial to understanding the principles that govern metalloprotein structure and function. Using the de novo designed TRI peptide family (TRI = Ac-G-(LKALEEK) 4 -G-NH 2 ), we have been investigating the influence of protein environment on metal-ion specificity and how subtle changes in the amino acid sequence can fully control the coordination number of the metal ion. By exploiting our previous observations that we could influence the metal binding affinity in the TRI coiled coils by placing cysteine in either position a or d of the heptad repeat unit, we designed a TRI derivative with two cysteine binding sites (TRI L9CL19C, Table 1) that shows sequential and selective binding of Cd II ions, first to the a site and then to the d site.[5]This result highlights how site-specific binding of Cd II ions can be achieved in a de novo designed peptide containing two binding sites that are defined by the same first-coordinationsphere ligands, three cysteine residues in both cases, solely by changing the conformation and environment of the metalbinding cavity. Later, using the a binding sites, we designed two peptides, TRI L16Pen and TRI L12AL16C (Table 1), that are able to bind Cd II ions exclusively in a trigonal-planar structure and a pseudotetrahedral geometry, respectively. This precise control of the coordination number and geometry of the Cd II centers was achieved by controlling the steric constraints in the metal-binding pocket. [6] We know that these complexes, [Cd(TRI L16Pen) While being able to impose a specific coordination number on a metal was a signal achievement, a more challenging construct would be a single polypeptide that utilizes subtle sequence pert...
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