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      Structural Analysis and Epitope Prediction of MHC Class-1-Chain Related Protein-A for Cancer Vaccine Development

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          Abstract

          Major histocompatibility complex class 1 chain-related gene sequence A is a polymorphic gene found at about 46.6 kb centromeric to HLA-B. It encodes a transmembrane protein, which is a non-classical human leukocyte antigen whose expression is normally induced by stress conditions like cancer and viral infections. The expression of MIC-A leads to the activation of NKG2D receptors of natural killer and T cells, leading to the generation of innate immune response that can easily eliminate/cleanse tumour cells and other cells that express the protein. Several bioinformatics and immunoinformatics tools were used to analyse the sequence and structure of the MIC-A protein. These tools were used in building and evaluating modelled structure of MIC-A, and to predict several antigenic determinant sites on the protein. The MIC-A protein structure generated an average antigenic propensity of 1.0289. Additionally, the hydrophilic regions on the surface of the MIC-A protein where antibodies can be attached were revealed. A total of fourteen antigenic epitopes were predicted, with six found in the transmembrane protein topology, and are predicted to play a role in the development of vaccines that can reactivate the functionalities of the MIC-A protein on the surface of cancer cells in order to elicit a desired immune response.

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          Most cited references23

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          Structure validation by Calpha geometry: phi,psi and Cbeta deviation.

          Geometrical validation around the Calpha is described, with a new Cbeta measure and updated Ramachandran plot. Deviation of the observed Cbeta atom from ideal position provides a single measure encapsulating the major structure-validation information contained in bond angle distortions. Cbeta deviation is sensitive to incompatibilities between sidechain and backbone caused by misfit conformations or inappropriate refinement restraints. A new phi,psi plot using density-dependent smoothing for 81,234 non-Gly, non-Pro, and non-prePro residues with B < 30 from 500 high-resolution proteins shows sharp boundaries at critical edges and clear delineation between large empty areas and regions that are allowed but disfavored. One such region is the gamma-turn conformation near +75 degrees,-60 degrees, counted as forbidden by common structure-validation programs; however, it occurs in well-ordered parts of good structures, it is overrepresented near functional sites, and strain is partly compensated by the gamma-turn H-bond. Favored and allowed phi,psi regions are also defined for Pro, pre-Pro, and Gly (important because Gly phi,psi angles are more permissive but less accurately determined). Details of these accurate empirical distributions are poorly predicted by previous theoretical calculations, including a region left of alpha-helix, which rates as favorable in energy yet rarely occurs. A proposed factor explaining this discrepancy is that crowding of the two-peptide NHs permits donating only a single H-bond. New calculations by Hu et al. [Proteins 2002 (this issue)] for Ala and Gly dipeptides, using mixed quantum mechanics and molecular mechanics, fit our nonrepetitive data in excellent detail. To run our geometrical evaluations on a user-uploaded file, see MOLPROBITY (http://kinemage.biochem.duke.edu) or RAMPAGE (http://www-cryst.bioc.cam.ac.uk/rampage). Copyright 2003 Wiley-Liss, Inc.
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            Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.

            Stress-inducible MICA, a distant homolog of major histocompatibility complex (MHC) class I, functions as an antigen for gammadelta T cells and is frequently expressed in epithelial tumors. A receptor for MICA was detected on most gammadelta T cells, CD8+ alphabeta T cells, and natural killer (NK) cells and was identified as NKG2D. Effector cells from all these subsets could be stimulated by ligation of NKG2D. Engagement of NKG2D activated cytolytic responses of gammadelta T cells and NK cells against transfectants and epithelial tumor cells expressing MICA. These results define an activating immunoreceptor-MHC ligand interaction that may promote antitumor NK and T cell responses.
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              Scalable web services for the PSIPRED Protein Analysis Workbench

              Here, we present the new UCL Bioinformatics Group’s PSIPRED Protein Analysis Workbench. The Workbench unites all of our previously available analysis methods into a single web-based framework. The new web portal provides a greatly streamlined user interface with a number of new features to allow users to better explore their results. We offer a number of additional services to enable computationally scalable execution of our prediction methods; these include SOAP and XML-RPC web server access and new HADOOP packages. All software and services are available via the UCL Bioinformatics Group website at http://bioinf.cs.ucl.ac.uk/.
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                Author and article information

                Journal
                Vaccines (Basel)
                Vaccines (Basel)
                vaccines
                Vaccines
                MDPI
                2076-393X
                25 December 2017
                March 2018
                : 6
                : 1
                : 1
                Affiliations
                [1 ]Biotechnology and Structural Biology (BSB) Group, Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, South Africa; adekiyatalex@ 123456gmail.com (T.A.A.); arulebataiwo@ 123456yahoo.com (R.T.A.); s7khanyile@ 123456gmail.com (S.K.); presh4u@ 123456rocketmail.com (P.M.); tunji4reele@ 123456yahoo.com (B.E.O.)
                [2 ]Department of Biochemistry, College of Sciences, Afe Babalola University, PMB 5454, Ado-Ekiti 360001, Nigeria
                Author notes
                [* ]Correspondence: KappoA@ 123456unizulu.ac.za ; Tel.: +27-35-902-6780; Fax: +27-35-902-6568
                Author information
                https://orcid.org/0000-0002-3382-9080
                https://orcid.org/0000-0003-0879-344X
                https://orcid.org/0000-0003-2521-8957
                Article
                vaccines-06-00001
                10.3390/vaccines6010001
                5874642
                29295563
                dc593b33-9888-4573-a064-1d9c4cced4d3
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 October 2017
                : 21 November 2017
                Categories
                Article

                antigenic peptides,bioinformatics,cancer,mic-a,vaccine,3-d structure,epitopes

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