scholarly journals QSalignWeb: A Server to Predict and Analyze Protein Quaternary Structure

2022 ◽  
Vol 8 ◽  
Author(s):  
Sucharita Dey ◽  
Jaime Prilusky ◽  
Emmanuel D. Levy

The identification of physiologically relevant quaternary structures (QSs) in crystal lattices is challenging. To predict the physiological relevance of a particular QS, QSalign searches for homologous structures in which subunits interact in the same geometry. This approach proved accurate but was limited to structures already present in the Protein Data Bank (PDB). Here, we introduce a webserver (www.QSalign.org) allowing users to submit homo-oligomeric structures of their choice to the QSalign pipeline. Given a user-uploaded structure, the sequence is extracted and used to search homologs based on sequence similarity and PFAM domain architecture. If structural conservation is detected between a homolog and the user-uploaded QS, physiological relevance is inferred. The web server also generates alternative QSs with PISA and processes them the same way as the query submitted to widen the predictions. The result page also shows representative QSs in the protein family of the query, which is informative if no QS conservation was detected or if the protein appears monomeric. These representative QSs can also serve as a starting point for homology modeling.

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2174 ◽  
Author(s):  
Annalisa Maruca ◽  
Delia Lanzillotta ◽  
Roberta Rocca ◽  
Antonio Lupia ◽  
Giosuè Costa ◽  
...  

Essential oils (EOs) are popular in aromatherapy, a branch of alternative medicine that claims their curative effects. Moreover, several studies reported EOs as potential anti-cancer agents by inducing apoptosis in different cancer cell models. In this study, we have considered EOs as a potential resource of new kinase inhibitors with a polypharmacological profile. On the other hand, computational methods offer the possibility to predict the theoretical activity profile of ligands, discovering dangerous off-targets and/or synergistic effects due to the potential multi-target action. With this aim, we performed a Structure-Based Virtual Screening (SBVS) against X-ray models of several protein kinases selected from the Protein Data Bank (PDB) by using a chemoinformatics database of EOs. By evaluating theoretical binding affinity, 13 molecules were detected among EOs as new potential kinase inhibitors with a multi-target profile. The two compounds with higher percentages in the EOs were studied more in depth by means Induced Fit Docking (IFD) protocol, in order to better predict their binding modes taking into account also structural changes in the receptor. Finally, given its good binding affinity towards five different kinases, cinnamyl cinnamate was biologically tested on different cell lines with the aim to verify the antiproliferative activity. Thus, this work represents a starting point for the optimization of the most promising EOs structure as kinase inhibitors with multi-target features.


2011 ◽  
Vol 39 (5) ◽  
pp. 1353-1358 ◽  
Author(s):  
Simon Newstead

One of the principal aims of modern drug design is the targeted delivery of drugs within the body, such as to the central nervous system, combined with their exclusion from the liver and kidneys, which break down foreign molecules and subsequently eliminate them. Many of the commonly prescribed drugs are transported into cells and across the plasma membrane via endogenous membrane transporters, whose principal roles are the uptake of essential nutrients for metabolism. In many cases, such drug transport is serendipitous as they are simply mistaken as ‘natural’ compounds. Many of these transporters could, however, be targeted more efficiently, improving drug absorption, distribution and retention. The molecular details of these drug–transporter interactions, however, are at best poorly understood, in large part through the absence of any high-resolution structural information. To address this issue, we recently determined the structure of a prokaryotic peptide transporter, PepTSo from Shewanella oneidensis, which shares a high degree of sequence similarity and functional characteristics with the human PepT1 and PepT2 proteins. PepT1 and PepT2 contribute significantly to the oral bioavailability and pharmacokinetic properties of a number of important drug families, including antibiotics, antivirals and anticancer agents. The crystal structure of PepTSo provides the first high-resolution model of a drug importer and provides the starting point for understanding drug and peptide transport within the human body.


Author(s):  
Florencia Claes ◽  
Alejandro Barranquero ◽  
Eduardo Rodríguez-Gómez

Research groups are professional structures that cooperate to produce knowledge and that must communicate their findings to make disciplines progress. This research analyzes how Spanish Communication research groups take advantage of the functionalities of the web 2.0 to transfer knowledge and promote closer collaboration with other academic entities. The starting point is an exhaustive census of research groups, prepared within the research project MapCom 2 and including groups belonging to communication faculties of public and private universities in Spain. Content analysis is then applied to examine how these groups use their respective websites, exploring six variables: navigability, dissemination of information and services, updating, international projection, SEO positioning, and possibilities of interaction with the audience. The analysis of the sites reveals disparate results in terms of the type of update, content, functionalities, and uses. Most of the groups listed have websites to present their lines of research and objectives. However, these spaces vary from one group to another (even within the same university), and many asymmetries can be detected in the information presented and in the fact that certain statements are not always accessible. The study of these variables –composed and designed for the present research– also allows us to analyze the knowledge transfer that the groups carry out, their possible level of interaction with citizens, or to determine whether they are more or less endogamic or have an external projection when promoting links with other members or groups at a local, state, or international level. The results show that Spanish groups have not yet managed to exploit the opportunities of the web 2.0 sufficiently to transfer knowledge as well as export and increase the visibility of their scientific production. Resumen Los grupos de investigación son estructuras académicas que cooperan para producir conocimiento y que necesitan comunicar sus hallazgos para fortalecer los campos y disciplinas científicas. La presente investigación analiza cómo los grupos españoles del campo de la Comunicación aprovechan las funciones de la web 2.0 para transferir el conocimiento y fomentar mecanismos de colaboración con otras entidades científicas. Se parte de la elaboración de un censo exhaustivo de grupos de investigación, elaborado en el marco del proyecto I+D MapCom 2, y que incluye grupos adscritos a las facultades de comunicación de universidades públicas y privadas en España. Se aplica un protocolo de análisis de contenido para estudiar cómo dichos grupos emplean sus webs en relación con seis variables: navegabilidad, exposición de informaciones y servicios, actualización, proyección internacional, trabajo de posicionamiento SEO, y posibilidades de interacción con el público. El análisis de las webs demuestra resultados dispares en cuanto a tipo de actualización, contenidos, funciones y usos. La mayoría de los grupos analizados cuenta con espacios online para exponer sus líneas de investigación y objetivos. Sin embargo, dichos espacios varían de un grupo a otro (e incluso dentro de la misma universidad), y se detectan abundantes asimetrías en la información expuesta y en el propio hecho de que ciertas declaraciones no son siempre accesibles. El estudio de estas variables –compuestas y diseñadas para la presente investigación– también nos permite analizar la transferencia de conocimiento que realizan los grupos, su nivel de interacción con la ciudadanía, y si estos son más o menos endogámicos o tienen una proyección externa al favorecer vínculos con otros miembros o grupos en escalas locales, estatales o internacionales. Los resultados demuestran que los grupos españoles aún no han conseguido explotar suficientemente la web 2.0 de cara a transferir conocimiento y visibilizar e internacionalizar su producción científica.


F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1395
Author(s):  
Shahram Mesdaghi ◽  
David L. Murphy ◽  
Filomeno Sánchez Rodríguez ◽  
J. Javier Burgos-Mármol ◽  
Daniel J. Rigden

Background: Recent strides in computational structural biology have opened up an opportunity to understand previously uncharacterised proteins.  The under-representation of transmembrane proteins in the Protein Data Bank highlights the need to apply new and advanced bioinformatics methods to shed light on their structure and function.  This study focuses on a family of transmembrane proteins containing the Pfam domain PF09335 ('SNARE_ASSOC'/ ‘VTT ‘/’Tvp38’). One prominent member, Tmem41b, has been shown to be involved in early stages of autophagosome formation and is vital in mouse embryonic development as well as being identified as a viral host factor of SARS-CoV-2. Methods: We used evolutionary covariance-derived information to construct and validate ab initio models, make domain boundary predictions and infer local structural features.  Results: The results from the structural bioinformatics analysis of Tmem41b and its homologues showed that they contain a tandem repeat that is clearly visible in evolutionary covariance data but much less so by sequence analysis.  Furthermore, cross-referencing of other prediction data with covariance analysis showed that the internal repeat features two-fold rotational symmetry.  Ab initio modelling of Tmem41b and homologues reinforces these structural predictions.  Local structural features predicted to be present in Tmem41b were also present in Cl-/H+ antiporters.  Conclusions: The results of this study strongly point to Tmem41b and its homologues being transporters for an as-yet uncharacterised substrate and possibly using H+ antiporter activity as its mechanism for transport.


2017 ◽  
Author(s):  
Morag R. Hunter ◽  
Geoffrey G. Hesketh ◽  
Anne-Claude Gingras ◽  
Stephen C. Graham

ABSTRACTMulti-subunit tethering complexes control membrane fusion events in eukaryotic cells. CORVET and HOPS are two such multi-subunit tethering complexes, both containing the Sec1/Munc18 protein subunit VPS33A. Metazoans additionally possess VPS33B, which has considerable sequence similarity to VPS33A but does not integrate into CORVET or HOPS complexes and instead stably interacts with VIPAR. It has been recently suggested that VPS33B and VIPAR comprise two subunits of a novel multi-subunit tethering complex (named ‘CHEVI’), analogous in configuration to CORVET and HOPS. We utilised the BioID proximity biotinylation assay to compare and contrast the interactomes of VPS33A and VPS33B. Overall, few proteins were identified as associating with both VPS33A and VPS33B, suggesting these proteins have distinct sub-cellular localisations. Consistent with previous reports, we observed that VPS33A was co-localised with many components of class III phosphatidylinositol 3-kinase (PI3KC3) complexes: PIK3C3, PIK3R4, NRBF2, UVRAG and RUBICON. Although in this assay VPS33A clearly co-localised with several subunits of CORVET and HOPS, no proteins with the canonical CORVET/HOPS domain architecture were found to co-localise with VPS33B. Instead, we identified two novel VPS33B-interacting proteins, VPS53 and CCDC22. CCDC22 co-immunoprecipitated with VPS33B and VIPAR in over-expression conditions and interacts directly with the VPS33B-VIPAR complex in vitro. However, CCDC22 does not appear to co-fractionate with VPS33B and VIPAR in gel filtration of human cell lysates. We also observed that the protein complex in HEK293T cells which contained VPS33B and VIPAR was considerably smaller than CORVET/HOPS, suggesting that, unlike VPS33A, VPS33B does not assemble into a large stable multi-subunit tethering complex.


2020 ◽  
Vol 49 (D1) ◽  
pp. D452-D457
Author(s):  
Lisanna Paladin ◽  
Martina Bevilacqua ◽  
Sara Errigo ◽  
Damiano Piovesan ◽  
Ivan Mičetić ◽  
...  

Abstract The RepeatsDB database (URL: https://repeatsdb.org/) provides annotations and classification for protein tandem repeat structures from the Protein Data Bank (PDB). Protein tandem repeats are ubiquitous in all branches of the tree of life. The accumulation of solved repeat structures provides new possibilities for classification and detection, but also increasing the need for annotation. Here we present RepeatsDB 3.0, which addresses these challenges and presents an extended classification scheme. The major conceptual change compared to the previous version is the hierarchical classification combining top levels based solely on structural similarity (Class > Topology > Fold) with two new levels (Clan > Family) requiring sequence similarity and describing repeat motifs in collaboration with Pfam. Data growth has been addressed with improved mechanisms for browsing the classification hierarchy. A new UniProt-centric view unifies the increasingly frequent annotation of structures from identical or similar sequences. This update of RepeatsDB aligns with our commitment to develop a resource that extracts, organizes and distributes specialized information on tandem repeat protein structures.


Author(s):  
Gabriel Jan Abrahams ◽  
Janet Newman

Crystallization is in many cases a critical step for solving the three-dimensional structure of a protein molecule. Determining which set of chemicals to use in the initial screen is typically agnostic of the protein under investigation; however, crystallization efficiency could potentially be improved if this were not the case. Previous work has assumed that sequence similarity may provide useful information about appropriate crystallization cocktails; however, the authors are not aware of any quantitative verification of this assumption. This research investigates whether, given current information, one can detect any correlation between sequence similarity and crystallization cocktails. BLAST was used to quantitate the similarity between protein sequences in the Protein Data Bank, and this was compared with three estimations of the chemical similarities of the respective crystallization cocktails. No correlation was detected between proteins of similar (but not identical) sequence and their crystallization cocktails, suggesting that methods of determining screens based on this assumption are unlikely to result in screens that are better than those currently in use.


Author(s):  
Stefano Benini

Abstract Together with genome analysis and knock-out mutants, structural and functional characterization of proteins provide valuable hints on the biology of the organism under investigation. Structural characterization can be achieved by techniques such as X-ray crystallography, NMR, Cryo-EM. The information derived from the structure are a good starting point to comprehend the details of the proteins molecular function for a better understanding of their biological role. This review aims at describing the progress in the structural and functional characterization of proteins from the plant pathogen Erwinia amylovora obtained by structural biology and currently deposited in the Protein Data Bank.


2000 ◽  
Vol 279 (2) ◽  
pp. L312-L318 ◽  
Author(s):  
Mala R. Chinoy ◽  
Steven E. Zgleszewski ◽  
Robert E. Cilley ◽  
Thomas M. Krummel

We have shown that dexamethasone (Dex) accelerates maturation and differentiation of cultured fetal murine lungs (Cilley RE, Zgleszewski SE, Krummel TM, and Chinoy MR. Surg Forum 47: 692–695, 1996). We now demonstrate that although Dex inhibits thinning of acinar walls and secondary septa formation, it does, however, promote lung growth. CD-1 murine fetal lungs were cultured for 7 days in the presence and absence of 10 nM Dex. Dex-modulated genes were investigated and identified by differential display of mRNAs performed with specific anchor primer H-T11G and 24 arbitrary primers. Thirty-five differentially expressed cDNAs were isolated, subcloned, sequenced, and identified through BLAST searches. One of these cDNAs, termed Dex2, with enhanced expression in Dex-treated lungs, had 100% similarity with ras-recision gene ( rrg), also known as the lysyl oxidase ( LOX) gene that encodes lysyl oxidase. LOX gene is very highly conserved, with significant sequence similarity among mouse, rat, and human. Two other cDNAs, termed Dex1 and Dex4, were also identified as rrg, with 92 and 97% sequence similarity with the existing data bank sequence of rrg. LOX enzyme is known to downregulate p21 ras protein and play a central role in the maturation of collagen and elastin in the extracellular matrix as well as modulate the cytoskeletal elements. Thus LOX may be important in lung developmental processes involving epithelial-mesenchymal interactions.


Molecules ◽  
2019 ◽  
Vol 24 (12) ◽  
pp. 2242 ◽  
Author(s):  
Jacob L. Bouchard ◽  
Taylor C. Davey ◽  
Todd M. Doran

Amyloid-β oligomers (AβOs) self-assemble into polymorphic species with diverse biological activities that are implicated causally to Alzheimer’s disease (AD). Synaptotoxicity of AβO species is dependent on their quaternary structure, however, low-abundance and environmental sensitivity of AβOs in vivo have impeded a thorough assessment of structure–function relationships. We developed a simple biochemical assay to quantify the relative abundance and morphology of cross-linked AβOs. We compared oligomers derived from synthetic Aβ40 (wild-type (WT) Aβ40) and a recombinant source, called Aβ(M1–40). Both peptides assemble into oligomers with common sizes and morphology, however, the predominant quaternary structures of Aβ(M1–40) oligomeric states were more diverse in terms of dispersity and morphology. We identified self-assembly conditions that stabilize high-molecular weight oligomers of Aβ(M1–40) with apparent molecular weights greater than 36 kDa. Given that mixtures of AβOs derived from both peptides have been shown to be potent neurotoxins that disrupt long-term potentiation, we anticipate that the diverse quaternary structures reported for Aβ(M1–40) oligomers using the assays reported here will facilitate research efforts aimed at isolating and identifying common toxic species that contribute to synaptic dysfunction.


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