Control of Metal Coordination Number in de Novo Designed Peptides through Subtle Sequence Modifications

Lee, Kyung Hoon; Matzapetakis, Manolis; Mitra, Soumya; Marsh, E. Neil G.; Pecoraro, Vincent L.

doi:10.1021/ja048839s

Cited by 52 publications

(87 citation statements)

References 17 publications

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“…Consequently, the supramolecular arrangement of MBPC-1 *Previous work by several groups has shown that various preexisting folds can be employed as stable scaffolds for hosting diverse metal coordination environments. Some of such engineered metalloproteins manifest properties characteristic of highly evolved natural systems, such as metal selectivity (30), redox tunability (31,32) as well as open coordination sites that allow for reactivity (33) and reversible small molecule binding (34). 1 These authors contributed equally to this work.…”

Section: Resultsmentioning

confidence: 99%

Metal templated design of protein interfaces

Salgado

Ambroggio

Brodin

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

130

156

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Metal coordination is a key structural and functional component of a large fraction of proteins. Given this dual role we considered the possibility that metal coordination may have played a templating role in the early evolution of protein folds and complexes. We describe here a rational design approach, Metal Templated Interface Redesign (MeTIR), that mimics the time course of a hypothetical evolutionary pathway for the formation of stable protein assemblies through an initial metal coordination event. Using a folded monomeric protein, cytochrome cb 562 , as a building block we show that its non-self-associating surface can be made self-associating through a minimal number of mutations that enable Zn coordination. The protein interfaces in the resulting Zn-directed, D 2 -symmetrical tetramer are subsequently redesigned, yielding unique protein architectures that self-assemble in the presence or absence of metals. Aside from its evolutionary implications, MeTIR provides a route to engineer de novo protein interfaces and metal coordination environments that can be tuned through the extensive noncovalent bonding interactions in these interfaces.evolution | metal coordination | protein self-assembly | protein-protein interactions | templating

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Section: Resultsmentioning

confidence: 99%

Metal templated design of protein interfaces

Salgado

Ambroggio

Brodin

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

130

156

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confidence: 99%

“…By removal of steric bulk above the plane of the Cys (replacing a Leu with an Ala, TRIL12AL16C), a cavity for a water molecule was achieved yielding a fully 4-coordinate CdS 3 O species (20). However, efforts to obtain 3-coordinate Cd(II) bound to Cys were unsuccessful (20,21). Ultimately, a pure CdS 3 environment was realized by resorting to the nonnatural amino acid analogue of Cys, penicillamine (Pen), in which bulky methyl groups replace the ␤-hydrogen atoms and are thought to exclude exogenous water from binding to the Cd(II).…”

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confidence: 99%

Using diastereopeptides to control metal ion coordination in proteins

Peacock

Hemmingsen

Pecoraro

2008

Proc. Natl. Acad. Sci. U.S.A.

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Here, we report a previously undescribed approach for controlling metal ion coordination geometry in biomolecules by reorientating amino acid side chains through substitution of L-to D-amino acids. These diastereopeptides allow us to manipulate the spatial orientation of amino acid side chains to alter the sterics of metal binding pockets. We have used this approach to design the de novo metallopeptide, Cd (TRIL12L DL16C)

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“…[4] In particular, we have asked whether the same metal can be bound to structurally related peptides with identical first-coordinationsphere ligands derived from the protein, but in one case form a trigonal structure and in a second case form a fourcoordinate pseudo-tetrahedral environment. [4] The relative importance of a metals geometric preference and the inherent protein structure is fundamental to understanding the folding, [5][6][7][8] stability, [9,10] and conformational changes [4,5,11] of metalloproteins, and hence the control of such site discrimination has been an important objective of protein design studies. The peptides described herein are variants of the TRI family of peptides shown in Table 1.…”

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confidence: 99%

“…The peptides described herein are variants of the TRI family of peptides shown in Table 1. The sequence of the TRI peptide is Ac-G(LKALEEK) 4 G-NH 2 . [12] A leucine residue at the hydrophobic layers is replaced by a cysteine residue at position 16 (TRI L16C) for generating a metal-binding site.…”

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confidence: 99%