scholarly journals STRUCTURAL COMPARISON OF PROKARYOTIC AND EUKARYOTIC FOLATE TRANSPORTERS BY COMPUTATIONAL APPROACH

2018 ◽  
Vol 11 (14) ◽  
pp. 19
Author(s):  
Deepa Agarwal ◽  
Alok Jha
Keyword(s):  
Homo Sapiens ◽  
New Drugs ◽  
Transmembrane Helices ◽  
Ramachandran Plot ◽  
Functional Prediction ◽  
Structural Comparison ◽  
Folate Receptors ◽  
Realistic Representation ◽  
Folate Transporters ◽  
Membrane Spanning

Objective: In silico approach has particularly drawn attention in providing a realistic representation needed to understand the fundamental molecular structure of a transporter. The importance of folate metabolism and role in the internalization of antifolates in eukaryotes have been studied extensively, but the structural study of folate transporters in Homo sapiens (HFT), Plasmodium falciparum (PFT), and Streptococcus sp. (SFT) is still lacking. This study was conducted to study and compare the structures of prokaryotic and eukaryotic folate transporters. Methods: HFT, PFT, and SFT were queried using blast and sequences were retrieved using National Center for Biotechnology and Information (NCBI) databases. This was superseded by structural and functional prediction of transporters. The structure has been generated using Swiss model which was visualized using PyMol and validated by Procheck and ERRAT analysis along with the values of different secondary structures mapping to diverse sections of the Ramachandran plot. The structural and functional comparison was performed by PROSO, ProFunc, TM Score, Porewalker, TMHMM, and Protscale. Result: All the parameters for structural comparison suggest that H. sapiens folate transporter is 16.67% and 17.72% identical to Plasmodium and Streptococcus whereas Plasmodium is 21.59% identical to Streptococcus. The evaluation of transmembrane helices and hydrophobicity resulted in the presence of 1, 4, and 12 membrane-spanning segments with predicted US, UDUD, and UDS as pore shape in Plasmodium, Streptococcus, and humans. Conclusion: Such folate receptors are the main targets for the specific conveyance of antifolates. The differences found between these species may offer possibilities for the development of new drugs in future. 

scholarly journals Modelo molecular teórico del receptor serotoninérgico 5HT2A acoplado a proteína G

2012 ◽  
Vol 17 (2) ◽  
pp. 119
Author(s):  
Rafael Eduardo Malagón Bernal ◽  
Manuel Alejandro Fernández Navas ◽  
Orlando Emilio Acevedo Sarmiento
Keyword(s):  
Theoretical Model ◽  
G Protein ◽  
Tertiary Structure ◽  
Homo Sapiens ◽  
Molecular Model ◽  
Ramachandran Plot ◽  
Bovine Rhodopsin ◽  
Protein Receptor ◽  
G Protein Coupled ◽  
Hydrophobicity Profile

<strong>Objective</strong> Build a theoretical molecular model of the tertiary structure of the Homo sapiens 5HT2A receptor from experimentally obtained structures as templates. <strong>Materials</strong> <strong>and methods</strong> In the construction of the theoretical model we considered the protocol established by Ballesteros and Weinstein for the construction of the G-protein coupled receptor, by the alignment of the amino acid sequence, hydrophobicity profiles, refinement of loops by spatial restrictions and energy minimization with the force field OPLS_2005. <strong>Results</strong> The resulting model was validated by the Ramachandran plot with 91.7% of amino acids within the limits set for angles phi and psi and a RMSD of 0.95 Å with respect to bovine rhodopsin. <strong>Conclusions</strong> We obtained a validated theoretical model useful in studies of ligand-receptor docking.<br /><strong>Key words</strong>: G protein receptor, hydrophobicity profile, Ramachandran plot, orthosteric site, molecular modelling.

scholarly journals Crystal structure of the PAS domain of the hEAG potassium channel

2016 ◽  
Vol 72 (8) ◽  
pp. 578-585 ◽  
Author(s):  
Xue Tang ◽  
Juan Shao ◽  
Xiaohong Qin
Keyword(s):  
Homo Sapiens ◽  
Cellular Responses ◽  
Structural Features ◽  
Pas Domain ◽  
Transmembrane Helices ◽  
Related Gene ◽  
Cellular Functions ◽  
Functional Roles ◽  
C Terminus ◽  
Β Sheet

KCNH voltage-gated potassium channels play critical roles in regulating cellular functions. The channel is composed of four subunits, each of which contains six transmembrane helices forming the central pore. The cytoplasmic parts of the subunits present a Per–Arnt–Sim (PAS) domain at the N-terminus and a cyclic nucleotide-binding homology domain at the C-terminus. PAS domains are conserved from prokaryotes to eukaryotes and are involved in sensing signals and cellular responses. To better understand the functional roles of PAS domains in KCNH channels, the structure of this domain from the humanether-à-go-gochannel (hEAG channel) was determined. By comparing it with the structures of theHomo sapiensEAG-related gene (hERG) channel and theDrosophilaEAG-like K+(dELK) channel and analyzing the structural features of the hEAG channel, it was identified that a hydrophobic patch on the β-sheet may mediate interaction between the PAS domain and other regions of the channel to regulate its functions.

A structural study of new potent and selective antagonists to the A2B adenosine receptor

2005 ◽  
Vol 61 (5) ◽  
pp. 569-576
Author(s):  
Valeria Ferretti ◽  
Loretta Pretto ◽  
Mojgan Aghazadeh Tabrizi ◽  
Valerio Bertolasi
Keyword(s):  
Side Effects ◽  
Structural Study ◽  
Adenosine Receptor ◽  
Structural Features ◽  
New Drugs ◽  
Receptor Subtypes ◽  
Structural Comparison ◽  
Crystallographic Study ◽  
Selective Antagonists ◽  
Enhanced Selectivity

Xanthines, including the natural derivatives theophylline and caffeine, are non-selective antagonists of adenosine. They are able to bind with good affinity to all four adenosine-receptor subtypes A1, A2A, A2B and A3. In order to develop new drugs with few side effects, over the last few years many efforts have been devoted to the discovery of new adenosine antagonists with enhanced selectivity properties. The present paper reports the crystal structures of five new xanthinic derivatives, which display different affinities and selectivity properties towards the A2B receptor. Besides the crystallographic study, a structural comparison has been made with the calculated geometry of other xanthinic derivatives which are reported to have similar biological characteristics to understand the structural features controlling their affinity capabilities and selectivity. This structural comparison has been interpreted in the light of a recently published study on the binding of N-benzo[1,3]-dioxol-5-yl-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1-H-pyrazol-3-iloxy]-acetamide to a model of the A2B receptor, which shows the most interesting affinity and selectivity properties.

scholarly journals Hypoxanthine phosphoribosyltransferase from Trypanosoma cruzi as a target for structure-based inhibitor design: crystallization and inhibition studies with purine analogs.

1997 ◽  
Vol 41 (8) ◽  
pp. 1686-1692 ◽  
Author(s):  
A E Eakin ◽  
A Guerra ◽  
P J Focia ◽  
J Torres-Martinez ◽  
S P Craig
Keyword(s):  
Trypanosoma Cruzi ◽  
De Novo ◽  
Homo Sapiens ◽  
Three Dimensional ◽  
New Drugs ◽  
Dimensional Structure ◽  
Hypoxanthine Phosphoribosyltransferase ◽  
Inhibitor Design ◽  
Purine Nucleotides ◽  
Purine Analogs

The hypoxanthine phosphoribosyltransferase (HPRT) from Trypanosoma cruzi is a potential target for enzyme structure-based inhibitor design, based on previous studies which indicate that these parasites lack the metabolic enzymes required for de novo synthesis of purine nucleotides. By using a bacterial complement selection system, 59 purine analogs were assayed for their interaction with the HPRTs from T. cruzi and Homo sapiens. Eight compounds were identified from the bacterial assay to have an affinity for the trypanosomal enzyme. Inhibition constants for four of these compounds against purified recombinant trypanosomal and human HPRTs were determined and compared. The results confirm that the recombinant system can be used to identify compounds which have affinity for the trypanosomal HPRT. Furthermore, the results provide evidence for the importance of chemical modifications at positions 6 and 8 of the purine ring in the binding of these compounds to the HPRTs. An accurate three-dimensional structure of the trypanosomal enzyme will greatly enhance our understanding of the interactions between HPRTs and these compounds. Toward this end, crystallization conditions for the trypanosomal HPRT and preliminary analysis of X-ray diffraction data to a resolution of 2 A is reported. These results represent significant progress toward a structure-based approach to the design of inhibitors of the HPRT of trypanosomes with the long-range goal of developing new drugs for the treatment of Chagas' disease.

Novel insights in folate receptors and transporters: implications for disease and treatment of immune diseases and cancer

Pteridines ◽  
2015 ◽  
Vol 26 (2) ◽  
pp. 41-53 ◽  
Author(s):  
Gerrit Jansen ◽  
Godefridus J. Peters
Keyword(s):  
Human Disease ◽  
Essential Role ◽  
Enzyme Regulation ◽  
Clinical Applications ◽  
Post Translational Modification ◽  
New Developments ◽  
Folate Receptors ◽  
Multidisciplinary Meeting ◽  
Folate Transporters ◽  
Scientific Interaction

AbstractFolate receptors and transporters as well as folate enzymes play an essential role in human disease and form important targets for the treatment of immune diseases and cancer. To discuss new developments in this area, every 2 years a multidisciplinary meeting is held, which aims to be an informal forum for fundamental scientists and clinicians. During this meeting, the regulation of folate transporters and folate enzymes is discussed at the level of expression, transcription, translation, post-translational modification, and splicing and enzyme regulation. Importantly, this knowledge is applied and translated into exciting clinical applications by clinicians with various backgrounds, such as surgeons, nephrologists, rheumatologists and oncologists. Moreover, the meeting provides an excellent forum for a scientific interaction between academia and industry.

scholarly journals The intracellular domain of homomeric glycine receptors modulates agonist efficacy

2020 ◽  
pp. jbc.RA119.012358 ◽  
Author(s):  
Josip Ivica ◽  
Remigijus Lape ◽  
Vid Jazbec ◽  
Jie Yu ◽  
Hongtao Zhu ◽  
...  
Keyword(s):  
Single Channel ◽  
Transmembrane Helix ◽  
Glycine Receptors ◽  
Transmembrane Helices ◽  
Structural Comparison ◽  
Open Probability ◽  
Partial Agonists ◽  
C Terminus ◽  
Intracellular Domains ◽  
Limited Sequence

Like other pentameric ligand-gated channels, glycine receptors (GlyRs) contain long intracellular domains (ICDs) between transmembrane helices 3 and 4. Structurally characterized GlyRs are generally engineered to have a very short ICD. We show here that for one such construct, zebrafish GlyREM, the agonists glycine, β-alanine, taurine, and GABA have high efficacy and produce maximum single-channel open probabilities greater than 0.9. In contrast, for full-length human α1 GlyR, taurine and GABA were clearly partial agonists, with maximum open probabilities of 0.46 and 0.09, respectively. We found that the elevated open probabilities in GlyREM are not due to the limited sequence differences between the human and zebrafish orthologs, but rather to replacement of the native ICD with a short tripeptide ICD. Consistent with this interpretation, shortening the ICD in the human GlyR increased the maximum open probability produced by taurine and GABA to 0.90 and 0.70, respectively, but further engineering it to resemble GlyREM (by introducing the zebrafish transmembrane helix 4 and C terminus) had no effect. Furthermore, reinstating the native ICD to GlyREM converted taurine and GABA to partial agonists, with maximum open probabilities of 0.66 and 0.40, respectively. Structural comparison of transmembrane helices 3 and 4 in short- and long-ICD GlyR subunits revealed that ICD shortening does not distort the orientation of these helices within each subunit. This suggests that the effects of shortening the ICD stem from removing a modulatory effect of the native ICD on GlyR gating, revealing a new role for ICD in pentameric ligand-gated channels.

scholarly journals A Network Flow Approach to Predict Protein Targets and Flavonoid Backbones to Treat Respiratory Syncytial Virus Infection

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
José Eduardo Vargas ◽  
Renato Puga ◽  
Joice de Faria Poloni ◽  
Luis Fernando Saraiva Macedo Timmers ◽  
Barbara Nery Porto ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Network Flow ◽  
Homo Sapiens ◽  
Topological Analysis ◽  
New Drugs ◽  
Viral Inhibition ◽  
Protein Targets ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Major Chemical

Background.Respiratory syncytial virus (RSV) infection is the major cause of respiratory disease in lower respiratory tract in infants and young children. Attempts to develop effective vaccines or pharmacological treatments to inhibit RSV infection without undesired effects on human health have been unsuccessful. However, RSV infection has been reported to be affected by flavonoids. The mechanisms underlying viral inhibition induced by these compounds are largely unknown, making the development of new drugs difficult.Methods.To understand the mechanisms induced by flavonoids to inhibit RSV infection, a systems pharmacology-based study was performed using microarray data from primary culture of human bronchial cells infected by RSV, together with compound-proteomic interaction data available forHomo sapiens.Results.After an initial evaluation of 26 flavonoids, 5 compounds (resveratrol, quercetin, myricetin, apigenin, and tricetin) were identified through topological analysis of a major chemical-protein (CP) and protein-protein interacting (PPI) network. In a nonclustered form, these flavonoids regulate directly the activity of two protein bottlenecks involved in inflammation and apoptosis.Conclusions.Our findings may potentially help uncovering mechanisms of action of early RSV infection and provide chemical backbones and their protein targets in the difficult quest to develop new effective drugs.

scholarly journals Structural basis for anion conduction in the calcium-activated chloride channel TMEM16A

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Cristina Paulino ◽  
Yvonne Neldner ◽  
Andy KM Lam ◽  
Valeria Kalienkova ◽  
Janine Denise Brunner ◽  
...  
Keyword(s):  
Chloride Channel ◽  
Functional Characterization ◽  
Structural Basis ◽  
Transmembrane Helices ◽  
Functional Behavior ◽  
The Family ◽  
Membrane Spanning ◽  
Similar Organization ◽  
Anion Conduction

The calcium-activated chloride channel TMEM16A is a member of a conserved protein family that comprises ion channels and lipid scramblases. Although the structure of the scramblase nhTMEM16 has defined the architecture of the family, it was unknown how a channel has adapted to cope with its distinct functional properties. Here we have addressed this question by the structure determination of mouse TMEM16A by cryo-electron microscopy and a complementary functional characterization. The protein shows a similar organization to nhTMEM16, except for changes at the site of catalysis. There, the conformation of transmembrane helices constituting a membrane-spanning furrow that provides a path for lipids in scramblases has changed to form an enclosed aqueous pore that is largely shielded from the membrane. Our study thus reveals the structural basis of anion conduction in a TMEM16 channel and it defines the foundation for the diverse functional behavior in the TMEM16 family.

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