Functional and structural studies of a Phospholipase A2-like protein complexed to zinc ions: Insights on its myotoxicity and inhibition mechanism

Borges, Rafael J.; Cardoso, Filomena; Fernandes, Carlos A. H.; Dreyer, Thiago R.; Moraes, Delkia Seabra de; Floriano, Rafael Stuani; Rodrigues‐Simioni, Léa; Fontes, Marcos R.M.

doi:10.1016/j.bbagen.2016.08.003

Cited by 25 publications

(31 citation statements)

References 69 publications

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Section: Resultsmentioning

confidence: 99%

“…MDiS is composed of residues 121 and 125, which are hydrophobic and exposed to the solvent in a short 3 10 helix, together with residues 122 and 123 24 . This secondary structure is stabilized by one hydrogen bond between the main chain atoms of residues 121 and 125 24 . K122 is the only conserved C-terminal residue among PLA 2 -like proteins, although the hydrophobic character of residues 121 and 125 is also conserved 14 .…”

Section: Resultsmentioning

confidence: 99%

“…In active state structures, both monomers are similar with this canonical conformation of MDiS (Tables 1 and 2 ). In inactive state structures, monomers are asymmetrical, with one in a non-canonical conformation and a dMDiS higher than 9 Å, as these residues are in an extended loop structure (Tables 1 and 2 ) 24 . Inact is the only inactive state structure with a non-canonical conformation, with a dMDiS of 8.5 Å; MDiS is in an intermediate state 24 .…”

Section: Resultsmentioning

confidence: 99%

“…The PLA 2 -like structures in the inactive state only contain the accessible hydrophobic channel in monomers that are in the canonical conformation with a volume ~266 Å 3 (Table 2 ). Curiously, the hydrophobic channels of the canonical monomers of BthTX-I/PEG400 and apo1 BthTX-I are closed by the side chain of H120, whereas they are open in the available models of other bothropic PLA 2 -like proteins 24 .…”

Section: Resultsmentioning

confidence: 99%

“…In the PLA 2 -like models, these sulphates interact with a cluster of basic residues on the C-terminus, called the membrane docking site (MDoS) 14 . The PLA 2 -like iFace is formed after these protein monomers are reoriented due to the entrance of hydrophobic molecules into the toxin hydrophobic channel 14 , 22 , 24 . With this allosteric activation, a cluster of hydrophobic residues is rearranged in both monomers to form the membrane disruption site (MDiS) 24 , which interacts with phospholipids and perturbs membrane integrity 14 .…”

Section: Introductionmentioning

confidence: 99%

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PLA2-like proteins myotoxic mechanism: a dynamic model description

Borges

Lemke

Fontes

2017

Sci Rep

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Phospholipase A2-like (PLA2-like) proteins contribute to the development of muscle necrosis in Viperidae snake bites and are not efficiently neutralized by current antivenom treatments. The toxic mechanisms of PLA2-like proteins are devoid of catalytic activity and not yet fully understood, although structural and functional experiments suggest a dimeric assembly and that the C-terminal residues are essential to myotoxicity. Herein, we characterized the functional mechanism of bothropic PLA2-like structures related to global and local measurements using the available models in the Protein Data Bank and normal mode molecular dynamics (NM-MD). Those measurements include: (i) new geometric descriptions between their monomers, based on Euler angles; (ii) characterizations of canonical and non-canonical conformations of the C-terminal residues; (iii) accessibility of the hydrophobic channel; (iv) inspection of ligands; and (v) distance of clustered residues to toxin interface of interaction. Thus, we described the allosteric activation of PLA2-like proteins and hypothesized that the natural movement between monomers, calculated from NM-MD, is related to their membrane disruption mechanism, which is important for future studies of the inhibition process. These methods and strategies can be applied to other proteins to help understand their mechanisms of action.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PLA2-like proteins myotoxic mechanism: a dynamic model description

Borges

Lemke

Fontes

2017

Sci Rep

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Use of diformyl‐triazolo Schiff base for Zn²⁺ sensing and intracellular live cell imaging

Maity

Bhunia

Patra

et al. 2023

Applied Organom Chemis

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A diformylphenol Schiff base of triazole‐amine, 4‐methyl‐2, 6‐bis‐[(1H‐[1,2,4] triazol‐3‐ylimino)‐methyl]‐phenol (PTR) has been synthesised and characterised by spectroscopic data (ESI‐MS, UV‐vis, FT‐IR, NMR spectra). The probe, PTR, emits at 610 nm upon excitation at 380 nm and the emission is strongly intensified on interacting with Zn2+ ion in DMSO‐water (99:1, v/v; HEPES buffer, pH, 7.2) solution even in the presence of 15 other cations (Cu2+, Mn2+, Co2+, Ni2+, Pd2+, Cd2+, Pb2+, Hg2+, Fe3+, Cr3+, Al3+, Na+, K+, Ba2+, Ca2+) and the emission band has been shifted to 530 nm. The limit of detection of Zn2+, 0.30 μM is much lower than WHO recommended value (76 μM). The binding constant (Kd) is 4.2585 × 104 M−1. Selective and sensitive chemosensing behaviour of PTR to Zn2+ has been explained by switching off ESIPT quenching of the keto‐enol tautomerisation of the probe along with the chelation enhancement of fluorescence (CHEF) by binding with Zn2+. The Job's plot and NMR titration have been extended to measure the 1:1 M composition [PTR + Zn2+]. The energy calculation by the DFT computation of keto and enol isomers supports easy tautomerisation and helps ESIPT quenching by proton transfer. Intracellular Zn2+ ions in living cells of HEK293 (PBS: phosphate buffer saline; pH, 7.2) have also been identified by the probe, PTR, using fluorescence microscopic imaging technique.

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Synthesis and photophysical investigation of Schiff base as a Mg²⁺ and Zn²⁺ fluorescent chemosensor and its application

Mei

wentao

et al. 2023

Luminescence

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In view of the fluorescent switching properties and anti-fatigue properties of diarylethene, a diarylethene fluorescent chemosensor for the immediate detection of zinc ion (Zn 2+ ) and magnesium ion (Mg 2+ ) in acetonitrile was synthesized in this article.The structure of 1o was determined by performing spectroscopy and elemental analysis. The presence of Zn 2+ or Mg 2+ made the chemosensor 1o show an obvious "turn-on" fluorescent signal (bright yellow-green for Mg 2+ and bright cyan for Zn 2+ ).The fluorescent change caused by the 1:1 binding of 1o and Zn 2+ or Mg 2+ might be due to hindering the excited-state intramolecular proton transfer (ESIPT) process, which were bolstered by Benesi-Hildebrand analysis, Job's plot curves, proton nuclear magnetic resonance ( 1 H-NMR) titration and mass spectrometry. The limits of detection were acquired from the standard curve plots for Mg 2+ at 44.6 nM and for Zn 2+ at 14 nM. Based on the fluorescent behaviors, a logic gate was constructed with the emission intensity at 528/518 nm as output signal, the ultraviolet-visible (UV-vis) lights, Mg 2+ /Zn 2+ and EDTA as input signals. Exogenous Zn 2+ and Mg 2+ fluorescent bioimaging were performed on Hela cells with 1o, indicating its potential application in biodiagnostic analysis. In particular, 1o was manufactured into test paper, and Zn 2+ or Mg 2+ can be conveniently, efficiently and qualitatively identified by the fluorescent color variation of the test strips.

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Functional and structural studies of a Phospholipase A2-like protein complexed to zinc ions: Insights on its myotoxicity and inhibition mechanism

Abstract: Zinc is a new candidate that can assist in anti-venom treatments and can promote the design of new and even more accurate structure-based inhibitors for PLA-like proteins.

Cited by 25 publications

References 69 publications

PLA2-like proteins myotoxic mechanism: a dynamic model description

PLA2-like proteins myotoxic mechanism: a dynamic model description

Use of diformyl‐triazolo Schiff base for Zn²⁺ sensing and intracellular live cell imaging

Synthesis and photophysical investigation of Schiff base as a Mg²⁺ and Zn²⁺ fluorescent chemosensor and its application

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Functional and structural studies of a Phospholipase A2-like protein complexed to zinc ions: Insights on its myotoxicity and inhibition mechanism

Abstract: Zinc is a new candidate that can assist in anti-venom treatments and can promote the design of new and even more accurate structure-based inhibitors for PLA-like proteins.

Cited by 25 publications

References 69 publications

PLA2-like proteins myotoxic mechanism: a dynamic model description

PLA2-like proteins myotoxic mechanism: a dynamic model description

Use of diformyl‐triazolo Schiff base for Zn2+ sensing and intracellular live cell imaging

Synthesis and photophysical investigation of Schiff base as a Mg2+ and Zn2+ fluorescent chemosensor and its application

Contact Info

Product

Resources

About

Use of diformyl‐triazolo Schiff base for Zn²⁺ sensing and intracellular live cell imaging

Synthesis and photophysical investigation of Schiff base as a Mg²⁺ and Zn²⁺ fluorescent chemosensor and its application