scholarly journals Structural Flexibility of the Macrophage Dengue Virus Receptor CLEC5A

2011 ◽  
Vol 286 (27) ◽  
pp. 24208-24218 ◽  
Author(s):  
Aleksandra A. Watson ◽  
Andrey A. Lebedev ◽  
Benjamin A. Hall ◽  
Angharad E. Fenton-May ◽  
Alexei A. Vagin ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Structural Information ◽  
Docking Studies ◽  
Binding Potential ◽  
Structural Flexibility ◽  
Dengue Virus Serotypes ◽  
Adapter Molecule ◽  
Dynamics Simulations ◽  
Β Sheet

The human C-type lectin-like molecule CLEC5A is a critical macrophage receptor for dengue virus. The binding of dengue virus to CLEC5A triggers signaling through the associated adapter molecule DAP12, stimulating proinflammatory cytokine release. We have crystallized an informative ensemble of CLEC5A structural conformers at 1.9-Å resolution and demonstrate how an on-off extension to a β-sheet acts as a binary switch regulating the flexibility of the molecule. This structural information together with molecular dynamics simulations suggests a mechanism whereby extracellular events may be transmitted through the membrane and influence DAP12 signaling. We demonstrate that CLEC5A is homodimeric at the cell surface and binds to dengue virus serotypes 1–4. We used blotting experiments, surface analyses, glycan microarray, and docking studies to investigate the ligand binding potential of CLEC5A with particular respect to dengue virus. This study provides a rational foundation for understanding the dengue virus-macrophage interaction and the role of CLEC5A in dengue virus-induced lethal disease.

scholarly journals Structural basis for the role of serine-rich repeat proteins from Lactobacillus reuteri in gut microbe–host interactions

2018 ◽  
Vol 115 (12) ◽  
pp. E2706-E2715 ◽  
Author(s):  
Saannya Sequeira ◽  
Devon Kavanaugh ◽  
Donald A. MacKenzie ◽  
Tanja Šuligoj ◽  
Samuel Walpole ◽  
...  
Keyword(s):  
Lactobacillus Reuteri ◽  
Structural Information ◽  
Bacterial Species ◽  
Surface Proteins ◽  
Structural Basis ◽  
Gene Encoding ◽  
Rhamnogalacturonan I ◽  
Host Microbe Interactions ◽  
Dynamics Simulations

Lactobacillus reuteri, a Gram-positive bacterial species inhabiting the gastrointestinal tract of vertebrates, displays remarkable host adaptation. Previous mutational analyses of rodent strain L. reuteri 100-23C identified a gene encoding a predicted surface-exposed serine-rich repeat protein (SRRP100-23) that was vital for L. reuteri biofilm formation in mice. SRRPs have emerged as an important group of surface proteins on many pathogens, but no structural information is available in commensal bacteria. Here we report the 2.00-Å and 1.92-Å crystal structures of the binding regions (BRs) of SRRP100-23 and SRRP53608 from L. reuteri ATCC 53608, revealing a unique β-solenoid fold in this important adhesin family. SRRP53608-BR bound to host epithelial cells and DNA at neutral pH and recognized polygalacturonic acid (PGA), rhamnogalacturonan I, or chondroitin sulfate A at acidic pH. Mutagenesis confirmed the role of the BR putative binding site in the interaction of SRRP53608-BR with PGA. Long molecular dynamics simulations showed that SRRP53608-BR undergoes a pH-dependent conformational change. Together, these findings provide mechanistic insights into the role of SRRPs in host–microbe interactions and open avenues of research into the use of biofilm-forming probiotics against clinically important pathogens.

scholarly journals Evolution Rescues Folding of Human Immunodeficiency Virus-1 Envelope Glycoprotein GP120 Lacking a Conserved Disulfide Bond

2008 ◽  
Vol 19 (11) ◽  
pp. 4707-4716 ◽  
Author(s):  
Rogier W. Sanders ◽  
Shang-Te D. Hsu ◽  
Eelco van Anken ◽  
I. Marije Liscaljet ◽  
Martijn Dankers ◽  
...  
Keyword(s):  
Disulfide Bond ◽  
Disulfide Bonds ◽  
Side Chain ◽  
Viral Glycoprotein ◽  
Immunodeficiency Virus ◽  
Glycoprotein Gp120 ◽  
Dynamics Simulations ◽  
Β Sheet

The majority of eukaryotic secretory and membrane proteins contain disulfide bonds, which are strongly conserved within protein families because of their crucial role in folding or function. The exact role of these disulfide bonds during folding is unclear. Using virus-driven evolution we generated a viral glycoprotein variant, which is functional despite the lack of an absolutely conserved disulfide bond that links two antiparallel β-strands in a six-stranded β-barrel. Molecular dynamics simulations revealed that improved hydrogen bonding and side chain packing led to stabilization of the β-barrel fold, implying that β-sheet preference codirects glycoprotein folding in vivo. Our results show that the interactions between two β-strands that are important for the formation and/or integrity of the β-barrel can be supported by either a disulfide bond or β-sheet favoring residues.

scholarly journals Molecular basis for the interaction between Integrator subunits IntS9 and IntS11 and its functional importance

2017 ◽  
Vol 114 (17) ◽  
pp. 4394-4399 ◽  
Author(s):  
Yixuan Wu ◽  
Todd R. Albrecht ◽  
David Baillat ◽  
Eric J. Wagner ◽  
Liang Tong
Keyword(s):  
Rna Polymerase Ii ◽  
Structural Information ◽  
Stable Complex ◽  
Small Nuclear Rna ◽  
Functional Studies ◽  
Enhancer Rna ◽  
Molecular Mechanism Of Action ◽  
Β Sheet ◽  
Two Hybrid

The metazoan Integrator complex (INT) has important functions in the 3′-end processing of noncoding RNAs, including the uridine-rich small nuclear RNA (UsnRNA) and enhancer RNA (eRNA), and in the transcription of coding genes by RNA polymerase II. The INT contains at least 14 subunits, but its molecular mechanism of action is poorly understood, because currently there is little structural information about its subunits. The endonuclease activity of INT is mediated by its subunit 11 (IntS11), which belongs to the metallo-β-lactamase superfamily and is a paralog of CPSF-73, the endonuclease for pre-mRNA 3′-end processing. IntS11 forms a stable complex with Integrator complex subunit 9 (IntS9) through their C-terminal domains (CTDs). Here, we report the crystal structure of the IntS9–IntS11 CTD complex at 2.1-Å resolution and detailed, structure-based biochemical and functional studies. The complex is composed of a continuous nine-stranded β-sheet with four strands from IntS9 and five from IntS11. Highly conserved residues are located in the extensive interface between the two CTDs. Yeast two-hybrid assays and coimmunoprecipitation experiments confirm the structural observations on the complex. Functional studies demonstrate that the IntS9–IntS11 interaction is crucial for the role of INT in snRNA 3′-end processing.

scholarly journals Comparative Docking Studies on Curcumin with COVID-19 Proteins

2020 ◽  
Author(s):  
Renuka Suravajhala ◽  
Abhinav Parashar ◽  
Babita Malik ◽  
Arun V. Nagaraj ◽  
Govindarajan Padmanaban ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Therapeutic Potential ◽  
Virus Disease ◽  
Rna Virus ◽  
Docking Studies ◽  
Binding Potential ◽  
Antiviral Protein ◽  
Repurposed Drugs ◽  
Role Of It

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a respiratory syndrome caused by positive RNA virus resulting in outbreak of corona virus disease 2019 (COVID-19). The SARS-CoV-2 genome and its association to SAR-CoV-1 vary from ca. 66% to 96% depending on the type of betacoronavirdeae family members. With several drugs, viz. chloroquine, hydroxychloroquine, ivermectin, quinidine, artemisinin, remdesivir, azithromycin considered for clinical trials, there has been an inherent need to find distinctive antiviral mechanisms of these drugs. On the other hand, curcumin, a natural bioactive molecule has been shown to have a therapeutic potential for various diseases, but no role of it in COVID-19 has been explored. In this work, we show the binding potential of curcumin targeted to a host of SARS-CoV-2 proteins, viz. spike glycoproteins (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17) along with nsp10 (PDB ID: 6W4H) and RNA dependent RNA polymerase (PDB ID: 6M71) structures. Our results indicate that curcumin has potential antiviral protein binding affinity towards SARS-CoV-2 proteins which is comparable with other repurposed drugs that are considered for clinical trials.

scholarly journals Bcl-xL dynamics and cancer-associated mutations under the lens of protein structure network and biomolecular simulations

2019 ◽  
Author(s):  
Valentina Sora ◽  
Elena Papaleo
Keyword(s):  
Protein Structure ◽  
Structural Information ◽  
Binding Pocket ◽  
Missense Mutations ◽  
Free Energies ◽  
Allosteric Communication ◽  
Explicit Solvent ◽  
Biomolecular Simulations ◽  
Dynamics Simulations

AbstractUnderstanding the finely orchestrated interactions leading to or preventing programmed cell death (apoptosis) is of utmost importance in cancer research since the failure of these systems could eventually lead to the onset of the disease. In this regard, the maintenance of a delicate balance between promoters and inhibitors of mitochondrial apoptosis is crucial, as demonstrated by the interplay among the Bcl-2 family members. Particularly, Bcl-xL is a target of interest due to its forefront role of its dysfunctions in cancer development. Bcl-xL prevents apoptosis by binding both the pro-apoptotic BH3-only proteins, as PUMA, and noncanonical partners such as p53 at different sites. An allosteric communication between the BH3-only proteins binding pocket and the p53 binding site has been postulated and supported by NMR and other biophysical data, mediating the release of p53 from Bcl-xL upon PUMA binding. The molecular details, especially at the residue level, of this mechanism remain unclear. In this work, we investigated the distal communication between these two sites in both Bcl-xL in its free state and bound to PUMA, and we evaluated how missense mutations of Bcl-xL found in cancer samples might impair the communication and thus the allosteric mechanism. We employed all-atom explicit solvent microsecond molecular dynamics simulations analyzed through a Protein Structure Network approach and integrated with calculations of changes in free energies upon cancer-related mutations identified by genomics studies. We found a subset of candidate residues responsible for both maintaining protein stability and for conveying structural information between the two binding sites and hypothesized possible communication routes between specific residues at both sites.

Docking Studies of Curcumin and Analogues with Various Phosphodiesterase 4 Subtypes

2020 ◽  
Vol 17 (2) ◽  
pp. 248-260 ◽  
Author(s):  
Yau Xin Yi ◽  
Anand Gaurav ◽  
Gabriel A. Akowuah
Keyword(s):  
Binding Affinity ◽  
Structural Information ◽  
Docking Studies ◽  
Side Chain ◽  
Data Set ◽  
Docking Analysis ◽  
Phosphodiesterase 4 ◽  
Curcumin Derivatives ◽  
Anti Inflammatory

Introduction: The primary aim of this study is to understand the binding of curcumin and its analogues to different PDE4 subtypes and identify the role of PDE4 subtype inhibition in the anti-inflammatory property of curcumin. Docking analysis has been used to acquire the above mentioned structural information and this has been further used for designing of curcumin derivatives with better anti-inflammatory activity. Materials and Methods: Curcumin and its analogues were subjected to docking using PDE4A, PDE4B, PDE4C and PDE4D as the targets. A data set comprising 18 analogues of curcumin, was used as ligands for docking of PDE4 subtypes. Curcumin was used as the standard for comparison. Docking was performed using AutoDock Vina 1.1.2 software integrated in LigandScout 4.1. During this process water molecules were removed from proteins, charges were added and receptor structures were minimised by applying suitable force fields. The docking scores were compared, and the selectivity of compounds for PDE4B over PDE4D was calculated as well. Results: All curcumin analogues used in the study showed good binding affinity with all PDE4 subtypes, with evident selectivity towards PDE4B subtype. Analogue A11 provides the highest binding affinity among all ligands. Conclusion: Curcumin and analogues have moderate to strong affinity towards all PDE4 subtypes and have evident selectivity towards PDE4B. The Oxygen atom of the methoxy group plays a key role in PDE4B binding and any alterations could interfere with the binding. Tetrahydropyran side chain and heterocyclic rings are also suggested to be helpful in PDE4B binding.

scholarly journals Altered Local Interactions and Long-Range Communications in UK Variant (B.1.1.7) Spike Glycoprotein

2021 ◽  
Vol 22 (11) ◽  
pp. 5464
Author(s):  
Stefano Borocci ◽  
Carmen Cerchia ◽  
Alessandro Grottesi ◽  
Nico Sanna ◽  
Ingrid Guarnetti Prandi ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Structural Information ◽  
Conformational Transitions ◽  
Structural Basis ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Dynamics Simulations ◽  
The Uk ◽  
The Impact

The COVID-19 pandemic is caused by SARS-CoV-2. Currently, most of the research efforts towards the development of vaccines and antibodies against SARS-CoV-2 were mainly focused on the spike (S) protein, which mediates virus entry into the host cell by binding to ACE2. As the virus SARS-CoV-2 continues to spread globally, variants have emerged, characterized by multiple mutations of the S glycoprotein. Herein, we employed microsecond-long molecular dynamics simulations to study the impact of the mutations of the S glycoprotein in SARS-CoV-2 Variant of Concern 202012/01 (B.1.1.7), termed the “UK variant”, in comparison with the wild type, with the aim to decipher the structural basis of the reported increased infectivity and virulence. The simulations provided insights on the different dynamics of UK and wild-type S glycoprotein, regarding in particular the Receptor Binding Domain (RBD). In addition, we investigated the role of glycans in modulating the conformational transitions of the RBD. The overall results showed that the UK mutant experiences higher flexibility in the RBD with respect to wild type; this behavior might be correlated with the increased transmission reported for this variant. Our work also adds useful structural information on antigenic “hotspots” and epitopes targeted by neutralizing antibodies.

Quantitative accuracy of serotonergic neurotrans-mission imaging with high-resolution 123I SPECT

2004 ◽  
Vol 43 (06) ◽  
pp. 185-189 ◽  
Author(s):  
J. T. Kuikka
Keyword(s):  
High Resolution ◽  
Scatter Correction ◽  
Region Of Interest ◽  
Binding Potential ◽  
Partial Volume ◽  
Therapeutic Drugs ◽  
Quantitative Accuracy ◽  
Critical Error ◽  
Statistical Noise

Summary Aim: Serotonin transporter (SERT) imaging can be used to study the role of regional abnormalities of neurotransmitter release in various mental disorders and to study the mechanism of action of therapeutic drugs or drugs’ abuse. We examine the quantitative accuracy and reproducibility that can be achieved with high-resolution SPECT of serotonergic neurotransmission. Method: Binding potential (BP) of 123I labeled tracer specific for midbrain SERT was assessed in 20 healthy persons. The effects of scatter, attenuation, partial volume, mis-registration and statistical noise were estimated using phantom and human studies. Results: Without any correction, BP was underestimated by 73%. The partial volume error was the major component in this underestimation whereas the most critical error for the reproducibility was misplacement of region of interest (ROI). Conclusion: The proper ROI registration, the use of the multiple head gamma camera with transmission based scatter correction introduce more relevant results. However, due to the small dimensions of the midbrain SERT structures and poor spatial resolution of SPECT, the improvement without the partial volume correction is not great enough to restore the estimate of BP to that of the true one.

The Role of Hydrophobicity in the Stability and pH-Switchability of (RXDX)4 and Coumarin-RXDX Conjugate β-Sheets

2020 ◽  
Author(s):  
Ryan Weber ◽  
Martin McCullagh
Keyword(s):  
Biological Imaging ◽  
Ph Sensing ◽  
Hydrophobic Residue ◽  
Ideal Candidate ◽  
Self Assembling ◽  
Sensing Applications ◽  
Β Sheets ◽  
The Stability ◽  
Dynamics Simulations

<p>pH-switchable, self-assembling materials are of interest in biological imaging and sensing applications. Here we propose that combining the pH-switchability of RXDX (X=Ala, Val, Leu, Ile, Phe) peptides and the optical properties of coumarin creates an ideal candidate for these materials. This suggestion is tested with a thorough set of all-atom molecular dynamics simulations. We first investigate the dependence of pH-switchabiliy on the identity of the hydrophobic residue, X, in the bare (RXDX)<sub>4</sub> systems. Increasing the hydrophobicity stabilizes the fiber which, in turn, reduces the pH-switchabilty of the system. This behavior is found to be somewhat transferable to systems in which a single hydrophobic residue is replaced with a coumarin containing amino acid. In this case, conjugates with X=Ala are found to be unstable and both pHs while conjugates with X=Val, Leu, Ile and Phe are found to form stable β-sheets at least at neutral pH. The (RFDF)<sub>4</sub>-coumarin conjugate is found to have the largest relative entropy value of 0.884 +/- 0.001 between neutral and acidic coumarin ordering distributions. Thus, we posit that coumarin-(RFDF)<sub>4</sub> containing peptide sequences are ideal candidates for pH-sensing bioelectronic materials.</p>

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