Structural analysis of a group III Glu62-phospholipase A2 from the scorpion, Mesobuthus tamulus: Targeting and reversible inhibition by native peptides

Hariprasad, Gururao; Kumar, Manoj; Srinivasan, Alagiri; Kaur, Punit; Singh, T.P.; Jithesh, O.

doi:10.1016/j.ijbiomac.2011.01.004

Cited by 25 publications

(22 citation statements)

References 39 publications

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“…The structures of all of the ligands were optimized using “Prepare Ligands" in Discovery Studio (DS) 2.1 (Accelrys Software, Inc., San Diego) [35], [36], [37]. The three-dimensional structure of ACE (PDB code 1O8A) was obtained from the Protein Data Bank [13].…”

Section: Methodsmentioning

confidence: 99%

Inhibition Mechanism and Model of an Angiotensin I-Converting Enzyme (ACE)-Inhibitory Hexapeptide from Yeast (Saccharomyces cerevisiae)

Liu

et al. 2012

PLoS ONE

101

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Angiotensin I-converting enzyme (ACE) has an important function in blood pressure regulation. ACE-inhibitory peptides can lower blood pressure by inhibiting ACE activity. Based on the sequence of an ACE-inhibitory hexapeptide (TPTQQS) purified from yeast, enzyme kinetics experiments, isothermal titration calorimetry (ITC), and a docking simulation were performed. The hexapeptide was found to inhibit ACE in a non-competitive manner, as supported by the structural model. The hexapeptide bound to ACE via interactions of the N-terminal Thr1, Thr3, and Gln4 residues with the residues on the lid structure of ACE, and the C-terminal Ser6 attracted the zinc ion, which is vital for ACE catalysis. The displacement of the zinc ion from the active site resulted in the inhibition of ACE activity. The structural model based on the docking simulation was supported by experiments in which the peptide was modified. This study provides a new inhibitory mechanism of ACE by a peptide which broads our knowledge for drug designing against enzyme targets.

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Section: Methodsmentioning

confidence: 99%

Inhibition Mechanism and Model of an Angiotensin I-Converting Enzyme (ACE)-Inhibitory Hexapeptide from Yeast (Saccharomyces cerevisiae)

Liu

et al. 2012

PLoS ONE

101

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“…Scorpion venom sPLA 2 belongs to group III and is composed of a long enzymatic chain and a short covalently fixed C-terminal chain generated after the release of five residues (penta-peptide) during the maturation processes [28]. Different members of group III sPLA 2 from scorpion venoms have been purified such as HfPLA 2 from Heterometrus fulvipes [29], MtPLA 2 from Mesobuthus tumulus [19] Imperatoxin (IpTxi) [16] and Phospholipin from…”

Section: Introductionmentioning

confidence: 99%

Functional characterization and FTIR-based 3D modeling of full length and truncated forms of Scorpio maurus venom phospholipase A 2

Krayem

Parsiegla

Gaussier

et al. 2018

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…Orientation of glutamate also rules out any possibility of a water mediated hydrogen bond formation. This type of conformational arrangement of residues at the active site is seen in PLA 2 enzymes in venom of scorpion [22]. In isoforms 4 and 5, there is a replacement of hydrophilic tyrosine to a Fig.…”

Section: Catalytic Sitementioning

confidence: 83%

Delineation of the Structural Elements of Oriental Liver Fluke PLA2 Isoforms for Potent Drug Designing

et al. 2013

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Clonorchis sinensis or the Chinese liver fluke is one of the most prevalent parasites affecting a major population in the oriental countries. The parasite lacks lipid generating mechanisms but is exposed to fatty acid rich bile in the liver. A secretory phospholipase A 2 , an enzyme that breaks down complex lipids, is important for the growth of the parasite. The enzyme is also implicated in the pathogenesis leading up to the hepatic fibrosis and its complications including cancer. The five isoforms of this particular enzyme from the parasite therefore qualify as potential drug targets. In this study, a detailed structural and ligand binding analysis of the isoforms has been done by modeling. The overall three dimensional structures of the isoforms are well conserved with three helices and a bwing stabilized by four disulfide bonds. There are characteristic differences at the calcium binding loop, hydrophobic channel and the C-terminal domain that can potentially be exploited for drug binding. But the most significant feature pertains to the catalytic site where the isoforms exhibit three variations of either a histidineaspartate-tyrosine or histidine-glutamate-tyrosine or histidine-aspartate-phenylalanine. Molecular docking studies show that isoform specific residues and their conformations in the substrate binding hydrophobic channel make unique interactions with certain inhibitor molecules resulting in a perfect tight fit. The proposed ligand molecules have a predicted affinity in micro-molar to nano-molar range. Interestingly, few of the ligand binding interaction patterns is in accordance to the phylogenetic studies to thereby establish the usefulness of evolutionary mechanisms in aiding ligand design. The molecular diversity of the parasitic PLA 2 described in this study provides a platform for personalized medicine in the therapeutics of clonorchiasis.

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Structural analysis of a group III Glu62-phospholipase A2 from the scorpion, Mesobuthus tamulus: Targeting and reversible inhibition by native peptides

Cited by 25 publications

References 39 publications

Inhibition Mechanism and Model of an Angiotensin I-Converting Enzyme (ACE)-Inhibitory Hexapeptide from Yeast (Saccharomyces cerevisiae)

Inhibition Mechanism and Model of an Angiotensin I-Converting Enzyme (ACE)-Inhibitory Hexapeptide from Yeast (Saccharomyces cerevisiae)

Functional characterization and FTIR-based 3D modeling of full length and truncated forms of Scorpio maurus venom phospholipase A 2

Delineation of the Structural Elements of Oriental Liver Fluke PLA2 Isoforms for Potent Drug Designing

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