Computational Prediction of a Putative Binding Site on Drp1: Implications for Antiparkinsonian Therapy

2014 ◽  
Vol 54 (7) ◽  
pp. 2042-2050 ◽  
Author(s):  
Hanumanthappa Pradeep ◽  
G. Krishnamurthy Rajanikant
Keyword(s):  
Binding Site ◽  
Computational Prediction ◽  
Putative Binding Site ◽  
Antiparkinsonian Therapy

Covalent-Fragment Screening of Brd4 Identifies a Ligandable Site Orthogonal to the Acetyl-Lysine Binding Sites

2019 ◽  
Author(s):  
Michael Olp ◽  
Daniel Sprague ◽  
Stefan Kathman ◽  
Ziyang Xu ◽  
Alexandar Statsyuk ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Binding Site ◽  
Binding Sites ◽  
Computational Prediction ◽  
Chemical Probes ◽  
Computational Docking ◽  
Fragment Screening ◽  
Covalent Inhibitors ◽  
Bet Protein ◽  
Proof Of Principle

<p>Brd4, a member of the bromodomain and extraterminal domain (BET) family, has emerged as a promising epigenetic target in cancer and inflammatory disorders. All reported BET family ligands bind within the bromodomain acetyl-lysine binding sites and competitively inhibit BET protein interaction with acetylated chromatin. Alternative chemical probes that act orthogonally to the highly-conserved acetyl-lysine binding sites may exhibit selectivity within the BET family and avoid recently reported toxicity in clinical trials of BET bromodomain inhibitors. Here, we report the first identification of a ligandable site on a bromodomain outside the acetyl-lysine binding site. Inspired by our computational prediction of hotspots adjacent to non-homologous cysteine residues within the <i>C</i>-terminal Brd4 bromodomain (Brd4-BD2), we performed a mid-throughput mass spectrometry screen to identify cysteine-reactive fragments that covalently and selectively modify Brd4. Subsequent mass spectrometry, NMR and computational docking analyses of electrophilic fragment hits revealed a novel ligandable site near Cys356 that is unique to Brd4 among all human bromodomains. This site is orthogonal to the Brd4-BD2 acetyl-lysine binding site as Cys356 modification did not impact binding of the pan-BET bromodomain inhibitor JQ1 in fluorescence polarization assays. Finally, we tethered covalent fragments to JQ1 and performed NanoBRET assays to provide proof of principle that this orthogonal site can be covalently targeted in intact human cells. Overall, we demonstrate the potential of targeting sites orthogonal to bromodomain acetyl-lysine binding sites to develop bivalent and covalent inhibitors that displace Brd4 from chromatin.</p>

scholarly journals Molecular Modeling of a Tandem Two Pore Domain Potassium Channel Reveals a Putative Binding Site for General Anesthetics

2014 ◽  
Vol 5 (12) ◽  
pp. 1246-1252 ◽  
Author(s):  
Edward J. Bertaccini ◽  
Robert Dickinson ◽  
James R. Trudell ◽  
Nicholas P. Franks
Keyword(s):  
Molecular Modeling ◽  
Potassium Channel ◽  
Binding Site ◽  
General Anesthetics ◽  
Pore Domain ◽  
Putative Binding Site

scholarly journals The role of Asp-107, the putative binding site of histamine, in histamine H1 receptor functions.

1994 ◽  
Vol 64 ◽  
pp. 168
Author(s):  
Kazumi Ota ◽  
Katsumi Fujimoto ◽  
Ikuo Imamura ◽  
Hideyuki Hayashi ◽  
Hiroyuki Kagamiyama ◽  
...  
Keyword(s):  
Binding Site ◽  
H1 Receptor ◽  
Histamine H1 Receptor ◽  
Putative Binding Site

scholarly journals Characterization of Amino Acid Substitutions in the Putative Binding Site of Bupropion in Glic

2020 ◽  
Vol 118 (3) ◽  
pp. 583a
Author(s):  
Dubem Onyejegbu ◽  
Jessica Shepherd ◽  
Elham Pirayesh ◽  
Akash Pandhare ◽  
Zackary R. Gallardo ◽  
...  
Keyword(s):  
Amino Acid ◽  
Binding Site ◽  
Amino Acid Substitutions ◽  
Putative Binding Site

scholarly journals A Putative Binding Site for Sp1 Is Involved in Transcriptional Regulation of CYP17 Gene Expression in Bovine Ovary*

Endocrinology ◽  
1997 ◽  
Vol 138 (5) ◽  
pp. 2011-2020 ◽  
Author(s):  
Raffaella Borroni ◽  
Zheng Liu ◽  
Evan R. Simpson ◽  
Margaret M. Hinshelwood
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Binding Site ◽  
Cyp17 Gene ◽  
Bovine Ovary ◽  
Putative Binding Site

scholarly journals Genetic disruption of the putative binding site for Homer on DmGluRA reduces sleep in Drosophila

SLEEP ◽  
2019 ◽  
Vol 43 (1) ◽  
Author(s):  
Sarah Ly ◽  
Ewa Strus ◽  
Nirinjini Naidoo
Keyword(s):  
Binding Site ◽  
Metabotropic Glutamate Receptors ◽  
Amino Acid Replacement ◽  
Sleep Regulation ◽  
Metabotropic Glutamate ◽  
Functional Homology ◽  
Group I ◽  
Homer Proteins ◽  
Physical Dissociation ◽  
Putative Binding Site

Abstract Homer proteins mediate plasticity and signaling at the postsynaptic density of neurons and are necessary for sleep and synaptic remodeling during sleep. The goal of this study was to investigate the mechanisms of sleep regulation by Homer signaling. Using the Drosophila animal model, we demonstrate that knockdown of Homer specifically in the brain reduces sleep and that Drosophila Homer binds to the sole Drosophila mGluR, known as DmGluRA. This is the first evidence that DmGluRA, which bears greatest homology to group II mammalian metabotropic glutamate receptors (mGluRs), shares functional homology with group I mGluRs which couple to Homer proteins in mammals. As sleep is associated with the physical dissociation of Homer and mGluRs proteins at the synapse, we sought to determine the functional necessity of Homer × DmGluRA interaction in sleep regulation. Using the CRISPR/Cas9 gene editing system, we generated a targeted amino acid replacement of the putative binding site for Homer on DmGluRA to prevent Homer and DmGluRA protein binding. We found that loss of the conserved proline-rich PPXXF sequence on DmGluRA reduces Homer/DmGluRA associations and significantly reduces sleep amount. Thus, we identify a conserved mechanism of synaptic plasticity in Drosophila and demonstrate that the interaction of Homer with DmGluRA is necessary to promote sleep.

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