The Predicted Binding Site and Dynamics of Peptide Inhibitors to the Methuselah GPCR fromDrosophila melanogaster†

ABSTRACT In order to predict the binding regions within the complex formed by Toll-like receptor 5 (TLR-5) and flagellin, a complementary hydropathy between the two proteins was sought. A region common to the flagellins of Salmonella enterica serovar Typhimurium, Pseudomonas aeruginosa, and Listeria monocytogenes was shown to be hydropathically complementary to the 552-to-561 fragment of TLR-5, whose sequence is EILDISRNQL. The hydrophobicity profile of this region is shared with flagellins of 377 bacterial species out of a total of 723 publicly available sequences. A conformational analysis of the predicted binding site of TLR-5, whose structure is still unknown, was carried out with a methodology already applied to similar problems. To sample the conformations available to the peptide chain, a plot of the number of conformations per unit energy interval (density of states) versus energy was built. Following a theoretical argument, conformations belonging to maxima in this plot were selected. The most stable structure obtained in this search, an α-helical conformation, was shown to form the electrostatic interactions Glu552-Gln89, Asp555-Arg92, and Arg558-Glu93 with the predicted binding site of the flagellin of S. enterica serovar Typhimurium, formed by the 88-to-97 chain fragment (LQRVRELAVQ), which is likewise α helical.

Download Full-text

Binding Ligands that Straddle an Important Contact Site on the RBD of the Covid-19 Spike Protein

10.1101/2020.08.03.234989 ◽

2020 ◽

Author(s):

Abraham Boyarsky

Keyword(s):

Monoclonal Antibody ◽

Binding Site ◽

Receptor Binding ◽

Exposure Therapy ◽

Peptide Inhibitors ◽

Binding Domain ◽

Spike Protein ◽

Receptor Binding Domain ◽

Contact Site ◽

Contact Residues

AbstractThe receptor binding domain (RBD) of the spike protein of the Covid-19 virus is responsible for attachment to human ACE2. A number of recent articles have studied monoclonal antibody blocking [8-11] and peptide inhibitors [12-16] of the Covid-19 virus. Here we report virtual ligand-based screening that targets pockets on each side of an important binding site with residues 502-504 on the RBD that contact residues 353-357 [15] of hACE2. These ligands are intended as pre-exposure therapy for Covid-19 infection.

Download Full-text

Identification of FOXO targets that generate diverse features of the diapause phenotype in the mosquito Culex pipiens

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1502751112 ◽

2015 ◽

Vol 112 (12) ◽

pp. 3811-3816 ◽

Cited By ~ 47

Author(s):

Cheolho Sim ◽

David S. Kang ◽

Sungshil Kim ◽

Xiaodong Bai ◽

David L. Denlinger

Keyword(s):

Binding Site ◽

Culex Pipiens ◽

Growth Regulation ◽

Hormone Signaling ◽

Forkhead Transcription Factor ◽

Chip Sequencing ◽

Physiological Pathways ◽

Functional Relevance ◽

Predicted Binding Site ◽

Do So

Insulin and juvenile hormone signaling direct entry of the mosquito Culex pipiens into its overwintering adult diapause, and these two critical signaling pathways appear to do so by converging on the regulation of forkhead transcription factor (FOXO). Diapause is a complex phenotype, and FOXO emerges as a prime candidate for activating many of the diverse physiological pathways that generate the diapause phenotype. Here, we used ChIP sequencing to identify direct targets of FOXO. The nearest gene in a 10-kb region surrounding a predicted binding site was extracted for each binding site, resulting in a dataset containing genes potentially regulated by FOXO. By selecting candidate genes based on their functional relevance to diapause, we identified five gene categories of potential interest, including stress tolerance, metabolic pathways, lifespan extension, cell cycle and growth regulation, and circadian rhythms. Twelve targets were prioritized for further analysis, 10 of which were validated by ChIP-quantitative PCR and quantitative real-time PCR. These 10 genes activated by FOXO are highly up-regulated during diapause and are thus strong candidates for implementation of the diapause syndrome.

Download Full-text

A Predicted Binding Site for Cholesterol on the GABAA Receptor

Biophysical Journal ◽

10.1016/j.bpj.2014.03.024 ◽

2014 ◽

Vol 106 (9) ◽

pp. 1938-1949 ◽

Cited By ~ 51

Author(s):

Jérôme Hénin ◽

Reza Salari ◽

Sruthi Murlidaran ◽

Grace Brannigan

Keyword(s):

Binding Site ◽

Gabaa Receptor ◽

Predicted Binding Site

Download Full-text

Modification of the glycine (co-activator) binding site of the N-methyl-?-aspartate receptor in the guinea pig fetus brain during development following hypoxia

Brain Research ◽

10.1016/s0006-8993(96)00528-8 ◽

1996 ◽

Vol 733 (1) ◽

pp. 15-20

Author(s):

B Razdan

Keyword(s):

Guinea Pig ◽

Binding Site ◽

Aspartate Receptor ◽

Methyl Aspartate ◽

Guinea Pig Fetus

Download Full-text

Antithrombin-mediated Inhibition of Factor Vlla-Tissue Factor Complex by the Synthetic Pentasaccharide Representing the Heparin Binding Site to Antithrombin

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650512 ◽

1996 ◽

Vol 76 (01) ◽

pp. 005-008 ◽

Cited By ~ 22

Author(s):

Jean Claude Lormeau ◽

Jean Pascal Herault ◽

Jean Marc Herbert

Keyword(s):

Binding Site ◽

Tissue Factor ◽

Residual Activity ◽

Coagulation Factors ◽

Heparin Binding ◽

Experimental Conditions ◽

First Order ◽

Heparin Binding Site ◽

Coagulant Activity

SummaryWe examined the effect of the synthetic pentasaccharide representing the minimal binding site of heparin to antithrombin on the antithrombin-mediated inactivation of factor Vila bound to tissue factor. This effect was compared to the effect of unfractionated heparin. Using purified recombinant human coagulation factors and either a clotting or an amidolytic assay for the determination of the residual activity of factor Vila, we showed that the pentasaccharide was an efficient antithrombin-dependent inhibitor of the coagulant activity of tissue factor-factor Vila complex. In our experimental conditions, assuming a mean MW of 14,000 for heparin, the molar pseudo-first order rate constants for ATIII-mediated FVIIa inhibition by ATIII-binding heparin and by the synthetic pentasaccharide were found to be similar with respective values of 104,000 ± 10,500 min-1 and 112,000 ± 12,000 min-1 (mean ± s.e.m., n = 3)

Download Full-text