Enzyme Adaptation to Inhibitor Binding:  A Cryptic Binding Site in PhenylethanolamineN-Methyltransferase

2007 ◽  
Vol 50 (20) ◽  
pp. 4845-4853 ◽  
Author(s):  
Christine L. Gee ◽  
Nyssa Drinkwater ◽  
Joel D. A. Tyndall ◽  
Gary L. Grunewald ◽  
Qian Wu ◽  
...  
Keyword(s):  
Binding Site ◽  
Inhibitor Binding ◽  
Enzyme Adaptation

scholarly journals Enzyme Adaptation to Inhibitor Binding: A Cryptic Binding Site in PhenylethanolamineN-Methyltransferase

2007 ◽  
Vol 50 (25) ◽  
pp. 6441-6441
Author(s):  
Christine L. Gee ◽  
Nyssa Drinkwater ◽  
Joel D. A. Tyndall ◽  
Gary L. Grunewald ◽  
Qian Wu ◽  
...  
Keyword(s):  
Binding Site ◽  
Inhibitor Binding ◽  
Enzyme Adaptation

scholarly journals Structural elements of a pH-sensitive inhibitor binding site in NMDA receptors

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Michael C. Regan ◽  
Zongjian Zhu ◽  
Hongjie Yuan ◽  
Scott J. Myers ◽  
Dave S. Menaldino ◽  
...  
Keyword(s):  
Nmda Receptors ◽  
Binding Site ◽  
Ph Sensitive ◽  
Structural Elements ◽  
Inhibitor Binding

scholarly journals Identification of Small Molecule Inhibitors of the Deubiquitinating Activity of the SARS-CoV-2 Papain-Like Protease: in silico Molecular Docking Studies and in vitro Enzymatic Activity Assay

2020 ◽  
Vol 8 ◽  
Author(s):  
Eleni Pitsillou ◽  
Julia Liang ◽  
Katherine Ververis ◽  
Kah Wai Lim ◽  
Andrew Hung ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Enzymatic Activity ◽  
Small Molecules ◽  
Binding Site ◽  
Protein Docking ◽  
Activity Assay ◽  
Epicatechin Gallate ◽  
Inhibitor Binding ◽  
Enzymatic Activity Assay

COVID-19 is an ongoing pandemic caused by the SARS-CoV-2 virus with important political, socio-economic, and public health consequences. Inhibiting replication represents an important antiviral approach, and in this context two viral proteases, the SARS-CoV-2 main and papain-like proteases (PLpro), which cleave pp1a and pp1ab polypeptides, are critical. Along with protease activity, the PLpro possesses deubiquitinating activity, which is important in immune regulation. Naphthalene-based inhibitors, such as the well-investigated GRL-0617 compound, have been shown to possess dual effects, inhibiting both protease and deubiquitinating activity of the PLpro. Rather than binding to the canonical catalytic triad, these type of non-covalent inhibitors target an adjacent pocket, the naphthalene-inhibitor binding site. Using a high-throughput screen, we have previously identified the dietary hypericin, rutin, and cyanidin-3-O-glucoside compounds as potential protease inhibitors targeting the naphthalene-inhibitor binding site. Here, our aim was to investigate the binding characteristics of these compounds to the PLpro, and to evaluate deubiquitinating activity, by analyzing seven different PLpro crystal structures. Molecular docking highlighted the relatively high affinity of GRL-0617 and dietary compounds. In contrast binding of the small molecules was abolished in the presence of ubiquitin in the palm subdomain of the PLpro. Further, docking the small molecules in the naphthalene-inhibitor binding site, followed by protein-protein docking revealed displacement of ubiquitin in a conformation inconsistent with functional activity. Finally, the deubiquitinating activity was validated in vitro using an enzymatic activity assay. The findings indicated that the dietary compounds inhibited deubiquitinase activity in the micromolar range with an order of activity of GRL-0167, hypericin >> rutin, cyanidin-3-O-glucoside > epigallocatechin gallate, epicatechin gallate, and cefotaxime. Our findings are in accordance with mechanisms and potential antiviral effects of the naphthalene-based, GRL-0617 inhibitor, which is currently progressing in preclinical trials. Further, our findings indicate that in particular hypericin, rutin, and cyanidin-3-O-glucoside, represent suitable candidates for subsequent evaluation as PLpro inhibitors.

Molecular Modelling of the Interaction of Cyanoacrylate Inhibitors with Photosystem II Part 2. The Effect of Stereochemistry of Inhibitor Binding

1993 ◽  
Vol 48 (9-10) ◽  
pp. 782-787 ◽  
Author(s):  
Simon P. Mackay ◽  
Patrick J. O’Malley
Keyword(s):  
Electron Transfer ◽  
Photosystem Ii ◽  
Binding Site ◽  
Energy Minimization ◽  
Electrostatic Interactions ◽  
D1 Protein ◽  
Spatial Arrangement ◽  
Inhibitor Binding ◽  
Protein Residues ◽  
Quinone Binding

Abstract The 2-cyanoacrylate inhibitors are a potent class of herbicides which block electron transfer in photosystem II. The spatial arrangement of different functional groups are an important factor in determining activity and a number of derivatives have been used as stereospecific probes of the secondary quinone binding site. More than one region of stereoselectivity in the binding site has been identified which influences the interaction with specific groups of the inhibitor. We have studied the interaction of various stereoisomers of the cyanoacrylates with the binding site in the D1 protein (residues Leu 210 to Val 280) by determining the nonbonded intermolecular energies between the modelled structures calculated by van der Waals and electrostatic interactions after energy minimization of the combined structures to reduce inter and intramolecular strain and have found that the results reflect the experimentally determined data

Probing the inhibitor-binding site of aldose reductase with site-directed mutagenesis

1998 ◽  
Vol 256 (2) ◽  
pp. 310-316 ◽  
Author(s):  
Thomas C. Hohman ◽  
Ossama El-Kabbani ◽  
Michael S. Malamas ◽  
Kehdih Lai ◽  
Tatiana Putilina ◽  
...  
Keyword(s):  
Binding Site ◽  
Aldose Reductase ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Inhibitor Binding

scholarly journals Identification of Serine 119 as an Effective Inhibitor Binding Site of M. tuberculosis Ubiquitin-like Protein Ligase PafA Using Purified Proteins and M. smegmatis

EBioMedicine ◽  
2018 ◽  
Vol 30 ◽  
pp. 225-236 ◽  
Author(s):  
He-Wei Jiang ◽  
Daniel M. Czajkowsky ◽  
Tao Wang ◽  
Xu-De Wang ◽  
Jia-bin Wang ◽  
...  
Keyword(s):  
Binding Site ◽  
Effective Inhibitor ◽  
Inhibitor Binding
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