scholarly journals Binding site multiplicity with fatty acid ligands: Implications for the regulation of PKR kinase autophosphorylation with palmitate

2014 ◽  
Vol 82 (10) ◽  
pp. 2429-2442 ◽  
Author(s):  
Liang Fang ◽  
Hyun Ju Cho ◽  
Christina Chan ◽  
Michael Feig
Keyword(s):  
Fatty Acid ◽  
Binding Site ◽  
Pkr Kinase

Identification of the fatty acid binding site on glutathione S-transferase P

1992 ◽  
Vol 189 (1) ◽  
pp. 197-205 ◽  
Author(s):  
Jun Nishihira ◽  
Teruo Ishibashi ◽  
Masaharu Sakai ◽  
Shinzo Nishi ◽  
Hidemasa Kondo ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Binding Site ◽  
Glutathione S Transferase ◽  
Fatty Acid Binding ◽  
Fatty Acid Binding Site

scholarly journals A Binding Site for Nonsteroidal Anti-inflammatory Drugs in Fatty Acid Amide Hydrolase

2012 ◽  
Vol 135 (1) ◽  
pp. 22-25 ◽  
Author(s):  
Laura Bertolacci ◽  
Elisa Romeo ◽  
Marina Veronesi ◽  
Paola Magotti ◽  
Clara Albani ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Binding Site ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

scholarly journals Characterizing the Fatty Acid Binding Site in the Cavity of Potassium Channel KcsA

Biochemistry ◽  
2012 ◽  
Vol 51 (40) ◽  
pp. 7996-8002 ◽  
Author(s):  
Natalie Smithers ◽  
Juan H. Bolivar ◽  
Anthony G. Lee ◽  
J. Malcolm East
Keyword(s):  
Fatty Acid ◽  
Potassium Channel ◽  
Binding Site ◽  
Fatty Acid Binding ◽  
Potassium Channel Kcsa ◽  
Fatty Acid Binding Site

scholarly journals Mechanism of Protein Kinase R Inhibition by Human Cytomegalovirus pTRS1

2016 ◽  
Vol 91 (5) ◽  
Author(s):  
Heather A. Vincent ◽  
Benjamin Ziehr ◽  
Nathaniel J. Moorman
Keyword(s):  
Protein Kinase ◽  
Binding Site ◽  
Human Cytomegalovirus ◽  
Kinase Activity ◽  
Critical Role ◽  
Binding Domain ◽  
Single Amino Acid ◽  
Protein Kinase R ◽  
Hcmv Disease ◽  
Pkr Kinase

ABSTRACT Double-stranded RNAs (dsRNA) produced during human cytomegalovirus (HCMV) infection activate the antiviral kinase protein kinase R (PKR), which potently inhibits virus replication. The HCMV pTRS1 and pIRS1 proteins antagonize PKR to promote HCMV protein synthesis and replication; however, the mechanism by which pTRS1 inhibits PKR is unclear. PKR activation occurs in a three-step cascade. First, binding to dsRNA triggers PKR homodimerizaton. PKR dimers then autophosphorylate, leading to a conformational shift that exposes the binding site for the PKR substrate eIF2α. Consistent with previous in vitro studies, we found that pTRS1 bound and inhibited PKR. pTRS1 binding to PKR was not mediated by an RNA intermediate, and mutations in the pTRS1 RNA binding domain did not affect PKR binding or inhibition. Rather, mutations that disrupted the pTRS1 interaction with PKR ablated the ability of pTRS1 to antagonize PKR activation by dsRNA. pTRS1 did not block PKR dimerization and could bind and inhibit a constitutively dimerized PKR kinase domain. In addition, pTRS1 binding to PKR inhibited PKR kinase activity. Single amino acid point mutations in the conserved eIF2α binding domain of PKR disrupted pTRS1 binding and rendered PKR resistant to inhibition by pTRS1. Consistent with a critical role for the conserved eIF2α contact site in PKR binding, pTRS1 bound an additional eIF2α kinase, heme-regulated inhibitor (HRI), and inhibited eIF2α phosphorylation in response to an HRI agonist. Together our data suggest that pTRS1 inhibits PKR by binding to conserved amino acids in the PKR eIF2α binding site and blocking PKR kinase activity. IMPORTANCE The antiviral kinase PKR plays a critical role in controlling HCMV replication. This study furthered our understanding of how HCMV evades inhibition by PKR and identified new strategies for how PKR activity might be restored during infection to limit HCMV disease.

scholarly journals Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands binding the Free Fatty Acid Pocket of SARS-CoV-2 Spike Protein

2020 ◽  
Author(s):  
Deborah Shoemark ◽  
Charlotte Colenso ◽  
Christine Toelzer ◽  
Kapil Gupta ◽  
Richard Sessions ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Binding Site ◽  
Spike Protein ◽  
Fatty Acid Binding ◽  
Open Conformation ◽  
Interaction Interface ◽  
Approved Drugs ◽  
Dynamics Simulations ◽  
Fatty Acid Binding Site

<p>Following our recent identification of a fatty acid binding site in the SARS-CoV-2 spike protein (Toelzer <i>et al., Science</i> eabd3255 (2020)), we investigate the binding of linoleate and other potential ligands at this site using molecular dynamics simulations. The results support the hypothesis that linoleate stabilises the locked form of the spike, in which its interaction interface for the ACE2 receptor is occluded. The simulations indicate weaker binding of linoleate to the partially open conformation. Simulations of dexamethasone bound at this site indicate that it binds similarly to linoleate, and thus may also stabilize a locked spike conformation. In contrast, simulations suggest that cholesterol bound at this site may destabilize the locked conformation, and in the open conformation, may preferentially bind at an alternative site in the hinge region between the receptor binding domain and the domain below, which could have functional relevance. We also use molecular docking to identify potential ligands that may bind at the fatty acid binding site, using the Bristol University Docking Engine (BUDE). BUDE docking successfully reproduces the linoleate complex and also supports binding of dexamethasone at the spike fatty acid site. Virtual screening of a library of approved drugs identifies vitamins D, K and A, as well as retinoid ligands with experimentally demonstrated activity against SARS-CoV-2 replication <i>in vitro</i>, as also potentially able to bind at this site. Our data suggest that the fatty acid binding site of the SARS-CoV-2 spike protein may bind a diverse array of candidate ligands. Targeting this site with small molecules, including dietary components such as vitamins, which may stabilise its locked conformation and represents a potential avenue for novel therapeutics or prophylaxis for COVID-19.</p>

scholarly journals The fatty acid site is coupled to functional motifs in the SARS-CoV-2 spike protein and modulates spike allosteric behaviour

2021 ◽  
Author(s):  
Ana Sofia Oliveira ◽  
Deborah Shoemark ◽  
Amaurys Avila Ibarra ◽  
Andrew D. Davidson ◽  
Imre Berger ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Binding Site ◽  
Acid Site ◽  
Host Cells ◽  
Spike Protein ◽  
Nonequilibrium Molecular Dynamics ◽  
Binding Motif ◽  
Fatty Acid Binding ◽  
Furin Cleavage Site ◽  
Fatty Acid Binding Site

The SARS-CoV-2 spike protein is the first contact point between the SARS-CoV-2 virus and host cells and mediates membrane fusion. Recently, a fatty acid binding site was identified in the spike (Toelzer et al. Science 2020). The presence of linoleic acid at this site modulates binding of the spike to the human ACE2 receptor, stabilizing a locked conformation of the protein. Here, dynamical-nonequilibrium molecular dynamics simulations reveal that this fatty acid site is coupled to functionally relevant regions of the spike, some of them far from the fatty acid binding pocket. Removal of a ligand from the fatty acid binding site significantly affects the dynamics of distant, functionally important regions of the spike, including the receptor-binding motif, furin cleavage site and fusion-peptide-adjacent regions. The results also show significant differences in behaviour between clinical variants of the spike: e.g. the D614G mutation shows a significantly different conformational response for some structural motifs relevant for binding and fusion. The simulations identify structural networks through which changes at the fatty acid binding site are transmitted within the protein. These communication networks significantly involve positions that are prone to mutation, indicating that observed genetic variation in the spike may alter its response to linoleate binding and associated allosteric communication.

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