MIPS: metal interactions in protein structures

Hemavathi, K.; Kalaivani, M.; Udayakumar, A.; Sowmiya, G.; Jeyakanthan, Jeyaraman; Sekar, K.

doi:10.1107/s002188980903982x

Cited by 23 publications

(15 citation statements)

References 13 publications

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“…But, in spite of aluminium being implicated as a trigger for the onset of Alzheimer's disease , very limited NMR studies involving aluminium have been reported. In a bioinformatics analysis carried out by us involving the residues of the Aβ12 fragment in various metal‐bound protein structures in the protein data bank , we find that there are very few aluminium‐bound structures reported as shown in Table S1. Of the reported structures, none are NMR structures.…”

Section: Discussionmentioning

confidence: 99%

Does Aluminium Bind to Histidine? An NMR Investigation of Amyloid β12 and Amyloid β16 Fragments

Narayan¹,

Krishnarjuna

Vishwanathan

et al. 2013

Chem Biol Drug Des

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Aluminium and zinc are known to be the major triggering agents for aggregation of amyloid peptides leading to plaque formation in Alzheimer's disease. While zinc binding to histidine in Aβ (amyloid β) fragments has been implicated as responsible for aggregation, not much information is available on the interaction of aluminium with histidine. In the NMR study of the N-terminal Aβ fragments, DAEFRHDSGYEV (Aβ12) and DAEFRHDSGYEVHHQK (Aβ16) presented here, the interactions of the fragments with aluminium have been investigated. Significant chemical shifts were observed for few residues near the C-terminus when aluminium chloride was titrated with Aβ12 and Aβ16 peptides. Surprisingly, it is nonhistidine residues which seem to be involved in aluminium binding. Based on NMR constrained structure obtained by molecular modelling, aluminium-binding pockets in Aβ12 were around charged residues such as Asp, Glu. The results are discussed in terms of native structure propagation, and the relevance of histidine residues in the sequences for metal-binding interactions. We expect that the study of such short amyloid peptide fragments will not only provide clues for plaque formation in aggregated conditions but also facilitate design of potential drugs for these targets.

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Section: Discussionmentioning

confidence: 99%

Does Aluminium Bind to Histidine? An NMR Investigation of Amyloid β12 and Amyloid β16 Fragments

Narayan¹,

Krishnarjuna

Vishwanathan

et al. 2013

Chem Biol Drug Des

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“…Programs that predict metal binding sites include FINDSITE-metal 35 , MetSite 36 , SVM-Prot 37 , SeqCHED 38 , and metalDetector 39 . Databases for querying metal binding sites include MESPEUS 16 , MIPS 40 , MDB 41 , MetalPDB 42 , Metal-MACiE 43 , MINAS (http://www.minas.uzh.ch/), and PROMISE 44 . The services PDBsum 45 and PDBeMotif 46 include additional annotations.…”

Section: Introductionmentioning

confidence: 99%

Validation of metal-binding sites in macromolecular structures with the CheckMyMetal web server

et al. 2013

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Metals play vital roles in both the mechanism and architecture of biological macromolecules. Yet structures of metal-containing macromolecules where metals are misidentified and/or suboptimally modeled are abundant in the Protein Data Bank (PDB). This shows the need for a diagnostic tool to identify and correct such modeling problems with metal binding environments. The "CheckMyMetal" (CMM) web server (http://csgid.org/csgid/metal_sites/) is a sophisticated, user-friendly web-based method to evaluate metal binding sites in macromolecular structures in respect to 7350 metal binding sites observed in a benchmark dataset of 2304 high resolution crystal structures. The protocol outlines how the CMM server can be used to detect geometric and other irregularities in the structures of metal binding sites and alert researchers to potential errors in metal assignment. The protocol also gives practical guidelines for correcting problematic sites by modifying the metal binding environment and/or redefining metal identity in the PDB file. Several examples where this has led to meaningful results are described in the anticipated results section. CMM was designed for a broad audience—biomedical researchers studying metal-containing proteins and nucleic acids—but is equally well suited for structural biologists to validate new structures during modeling or refinement. The CMM server takes the coordinates of a metal-containing macromolecule structure in the PDB format as input and responds within a few seconds for a typical protein structure modeled with a few hundred amino acids.

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“…without any other protein residue being involved. We narrowed these hits to tri-Asp sites in proteins at three-fold symmetry axes and combined them with hits from other searches using MIPS 26 , MetalS3 27 , and Metalmine 28 resulting in 14 sites, including LarE (Fig. 3).…”

Section: Crystallographic Characterization Of Metal Binding To the Trmentioning

confidence: 99%

Crystallographic characterization of a tri-Asp metal-binding site at the three-fold symmetry axis of LarE

Fellner

Huizenga

Hausinger

et al. 2020

Sci Rep

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Detailed crystallographic characterization of a tri-aspartate metal-binding site previously identified on the threefold symmetry axis of a hexameric enzyme, LarE from Lactobacillus plantarum, was conducted. By screening an array of monovalent, divalent, and trivalent metal ions, we demonstrated that this metal binding site stoichiometrically binds ca 2+ , Mn 2+ , Fe 2+ /fe 3+ , Co 2+ , Ni 2+ , Cu 2+ , Zn 2+ , and cd 2+ , but not monovalent metal ions, Cr 3+ , Mg 2+ , Y 3+ , Sr 2+ or Ba 2+. Extensive database searches resulted in only 13 similar metal binding sites in other proteins, indicative of the rareness of triaspartate architectures, which allows for engineering such a selective multivalent metal ion binding site into target macromolecules for structural and biophysical characterization. Metals are essential components of many biological macromolecules, especially proteins. About a third 1,2 of the protein structures in the PDB 3 contain one or more metal atoms. The atomic structures of metal-containing cofactors and other metal-binding sites often provide insights into molecular mechanisms and/or reveal critical structural roles. Ten metal cations Mg 2+ , K + , Ca 2+ , Mn 2+ , Fe 2+ , Co 2+ , Ni 2+ , Cu 2+/+ , and Zn 2+ are commonly associated with proteins 4 , but other elements also may play important roles in catalysis or are associated with toxic effects 1. Because of their unique spectroscopic characteristics, some transition metals have been used to study structural and dynamics properties of macromolecules 5-7. In this study, we present a crystallographic analysis of a recently discovered 8 tri-Asp metal-binding site on the threefold symmetry axis of the hexameric LarE protein from Lactobacillus plantarum. LarE 8,9 , a member of the PP-loop ATP pyrophosphatase family 10 , in conjunction with LarB 11,12 and LarC 13 , participates in the synthesis of the nickel-pincer nucleotide cofactor of lactate racemase 14-17. Our crystallographic studies indicated binding specificity towards certain divalent or trivalent metal ions. An extensive database search for similar metal binding sites in other proteins resulted in only 13 hits and structural comparison among these sites revealed the uniqueness of the tri-Asp site in LarE. Given its rarity in protein structures, we propose that such a metal binding site can be engineered into macromolecules 18,19 of interest to facilitate structural and biophysical characterization.

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MIPS: metal interactions in protein structures

Cited by 23 publications

References 13 publications

Does Aluminium Bind to Histidine? An NMR Investigation of Amyloid β12 and Amyloid β16 Fragments

Does Aluminium Bind to Histidine? An NMR Investigation of Amyloid β12 and Amyloid β16 Fragments

Validation of metal-binding sites in macromolecular structures with the CheckMyMetal web server

Crystallographic characterization of a tri-Asp metal-binding site at the three-fold symmetry axis of LarE

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