scholarly journals in silico Study Reveals Potential Docking Sites of δ 2-isoxazolines derivates for Inhibiting Russell’s Viper PLA2 Toxin

2021 ◽  
Vol 11 (1) ◽  
pp. 45-51
Author(s):  
Tsaniyah Kholilah ◽  
◽  
Nashi Widodo ◽  
Nia Kurniawan ◽  
◽  
...  
Keyword(s):  
Active Site ◽  
Therapeutic Strategy ◽  
Inhibitor Activity ◽  
In Silico Study ◽  
Pharmacological Interest ◽  
Snake Venom Phospholipase ◽  
Serum Therapy ◽  
Human Use ◽  
Russell’S Viper ◽  
Active Site Region

Snake venom phospholipase A2s (svPLA2s) has been known as the most abundant component and predominant cause of Russell’s viper envenomation. Limitation to serum therapy and considerable pharmacological interest led the researcher to synthesized multi-toxic PLA2 inhibitors, δ2-isoxazolines derivate. Although δ2- isoxazolines derivate already proved inhibitor activity in Group II svPLA2 with known IC50, their mechanism of action remains unveiled. Our recent study investigated their inhibitory activity via molecular docking. The virtual screening revealed that the ligand with diverse structures tied to the relatively same active site region. The result sheds light on the significance of His48 and Asp49 as part of the pro-inflammatory eliciting region. ADME analysis was also performed to filter and identify the best potential inhibitor acceptable for human use. This moiety leads to finding a better therapeutic strategy of svPLA2 inhibitors both as an alternative to serum anti-venom treatment.

scholarly journals Activity of linked HIV-1 proteinase dimers containing mutations in the active site region

1996 ◽  
Vol 9 (11) ◽  
pp. 997-1003 ◽  
Author(s):  
Péter Bagossi ◽  
Yin-Shyun E. Cheng ◽  
Stephen Oroszlan ◽  
József Tözsér
Keyword(s):  
Active Site ◽  
Active Site Region ◽  
Hiv 1

scholarly journals A crystallographic study of the Toho-1 β-lactamase acylation mechanism

2014 ◽  
Vol 70 (a1) ◽  
pp. C1207-C1207
Author(s):  
Leighton Coates
Keyword(s):  
Hydrogen Bonding ◽  
Transition State ◽  
Active Site ◽  
Catalytic Mechanism ◽  
Substrate Binding ◽  
Ligand Complex ◽  
Transition State Analog ◽  
Hydrogen Bonding Interactions ◽  
Active Site Region ◽  
Neutron Crystallography

β-lactam antibiotics have been used effectively over several decades against many types of highly virulent bacteria. The predominant cause of resistance to these antibiotics in Gram-negative bacterial pathogens is the production of serine β-lactamase enzymes. A key aspect of the class A serine β-lactamase mechanism that remains unresolved and controversial is the identity of the residue acting as the catalytic base during the acylation reaction. Multiple mechanisms have been proposed for the formation of the acyl-enzyme intermediate that are predicated on understanding the protonation states and hydrogen-bonding interactions among the important residues involved in substrate binding and catalysis of these enzymes. For resolving a controversy of this nature surrounding the catalytic mechanism, neutron crystallography is a powerful complement to X-ray crystallography that can explicitly determine the location of deuterium atoms in proteins, thereby directly revealing the hydrogen-bonding interactions of important amino acid residues. Neutron crystallography was used to unambiguously reveal the ground-state active site protonation states and the resulting hydrogen-bonding network in two ligand-free Toho-1 β-lactamase mutants which provided remarkably clear pictures of the active site region prior to substrate binding and subsequent acylation [1,2] and an acylation transition-state analog, benzothiophene-2-boronic acid (BZB), which was also isotopically enriched with 11B. The neutron structure revealed the locations of all deuterium atoms in the active site region and clearly indicated that Glu166 is protonated in the BZB transition-state analog complex. As a result, the complete hydrogen-bonding pathway throughout the active site region could then deduced for this protein-ligand complex that mimics the acylation tetrahedral intermediate [3].

scholarly journals Digital dissection of arsenate reductase enzyme from an arsenic hyperccumulating fern Pteris vittata

2016 ◽  
Author(s):  
Zarrin Basharat ◽  
Deeba Noreen Baig ◽  
Azra Yasmin
Keyword(s):  
Neural Network ◽  
Active Site ◽  
Tertiary Structure ◽  
Pteris Vittata ◽  
Arsenate Reductase ◽  
Dynamics Simulation ◽  
Reduction Mechanism ◽  
Arsenic Reduction ◽  
Secondary And Tertiary Structure ◽  
Active Site Region

Action of arsenate reductase is crucial for the survival of an organism in arsenic polluted area. Pteris vittata, also known as Chinese ladder brake, was the first identified arsenic hyperaccumulating fern with the capability to convert [As(V)] to arsenite [As(III)]. This study aims at sequence analysis of the most important protein of the arsenic reduction mechanism in this specie. Phosphorylation potential of the protein along with possible interplay of phosphorylation with O-β-GlcNAcylation was predicted using neural network based webservers. Secondary and tertiary structure of arsenate reductase was then analysed. Active site region of the protein comprised a rhodanese-like domain. Cursory dynamics simulation revealed that folds remained conserved in the rhodanese main but variations were observed in the structure in other regions. This information sheds light on the various characteristics of the protein and may be useful to enzymologists working on the improvement of its traits for arsenic reduction.

scholarly journals The Non-Coding B2 RNA Binds to the DNA Cleft and Active-Site Region of RNA Polymerase II

2013 ◽  
Vol 425 (19) ◽  
pp. 3625-3638 ◽  
Author(s):  
Steven L. Ponicsan ◽  
Stephane Houel ◽  
William M. Old ◽  
Natalie G. Ahn ◽  
James A. Goodrich ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Active Site ◽  
B2 Rna ◽  
Active Site Region

Crystallographic observations of the metal ion triple in the active site region of alkaline phosphatase

1983 ◽  
Vol 170 (2) ◽  
pp. 575-581 ◽  
Author(s):  
Janusz M. Sowadski ◽  
Mark D. Handschumacher ◽  
H.M. Krishna Murthy ◽  
Caraig E. Kundrot ◽  
Harold W. Wyckoff
Keyword(s):  
Alkaline Phosphatase ◽  
Active Site ◽  
Metal Ion ◽  
Active Site Region

scholarly journals TraR directly regulates transcription initiation by mimicking the combined effects of the global regulators DksA and ppGpp

2017 ◽  
Vol 114 (28) ◽  
pp. E5539-E5548 ◽  
Author(s):  
Saumya Gopalkrishnan ◽  
Wilma Ross ◽  
Albert Y. Chen ◽  
Richard L. Gourse
Keyword(s):  
Active Site ◽  
Transcription Initiation ◽  
Coiled Coil ◽  
Global Regulator ◽  
Secondary Channel ◽  
Global Regulators ◽  
Extrachromosomal Elements ◽  
Distant Homolog ◽  
Active Site Region

TheEscherichia coliF element-encoded protein TraR is a distant homolog of the chromosome-encoded transcription factor DksA. Here we address the mechanism by which TraR acts as a global regulator, inhibiting some promoters and activating others. We show that TraR regulates transcription directly in vitro by binding to the secondary channel of RNA polymerase (RNAP) using interactions similar, but not identical, to those of DksA. Even though it binds to RNAP with only slightly higher affinity than DksA and is only half the size of DksA, TraR by itself inhibits transcription as strongly as DksA and ppGpp combined and much more than DksA alone. Furthermore, unlike DksA, TraR activates transcription even in the absence of ppGpp. TraR lacks the residues that interact with ppGpp in DksA, and TraR binding to RNAP uses the residues in the β′ rim helices that contribute to the ppGpp binding site in the DksA–ppGpp–RNAP complex. Thus, unlike DksA, TraR does not bind ppGpp. We propose a model in which TraR mimics the effects of DksA and ppGpp together by binding directly to the region of the RNAP secondary channel that otherwise binds ppGpp, and its N-terminal region, like the coiled-coil tip of DksA, engages the active-site region of the enzyme and affects transcription allosterically. These data provide insights into the function not only of TraR but also of an evolutionarily widespread and diverse family of TraR-like proteins encoded by bacteria, as well as bacteriophages and other extrachromosomal elements.

Mapping of Allosteric Modulator Effects in the Active Site of Factor IXa.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2695-2695
Author(s):  
Karla Villegas ◽  
Kimberly Baker-Deadmond ◽  
Pierre F. Neuenschwander
Keyword(s):  
Ethylene Glycol ◽  
Active Site ◽  
Allosteric Modulation ◽  
Factor Ix ◽  
Ionic Calcium ◽  
Gla Domain ◽  
A Site ◽  
Hydrolysis Of ◽  
Insight Into ◽  
Active Site Region

Abstract Activated factor IX (fIXa) is a vitamin K-dependent blood coagulation serine protease involved in propagation of the coagulant response through activation of fX. Maximal enzymatic and procoagulant activity of fIXa requires the presence of several cofactors; one of which is ionic calcium, which is known to bind to a site in the protease domain of fIXa as well as several sites within the light chain Gla domain region. One of the roles of calcium appears to be allosteric modulation of the fIXa active site as evidenced by an increase in enzymatic activity towards small peptidyl substrates. We and others have additionally found that certain small hygroscopic molecules can also enhance fIXa amidolytic activity. The molecular details involved in either of these effects are not well understood. Previous studies by us have shown that a pentapeptide substrate (AGRSL; the reactive site sequence of antithrombin) is hydrolyzed by fIXa in the absence of cofactors or modulators. This hydrolysis is enhanced in the presence of ionic calcium, ethylene glycol or low molecular weight heparin suggesting effects of these molecules on the immediate active site vicinity of fIXa. In order to gain insight into the potential allosteric modulation that each of these effectors may affect in fIXa, we examined the hydrolysis of four peptide libraries based on the AGRSL pentapeptide sequence, in the presence and absence of various fIXa modulators. The four libraries synthesized were XGRSL, AXRSL, AGRXL and AGRSX; where X denotes any of the possible 20 amino acids. Each of these libraries were screened for hydrolysis by fIXa under various conditions with substrates and products being identified en masse using MALDI-TOF mass spectrometry. The results suggest that ionic calcium enhances fIXa reactivity in part by modulation of the S2 subsite in fIXa. In contrast, ethylene glycol enhances fIXa activity via modulation of the S3 subsite and heparin was found to effect the overall active site region.

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