Highly active antiretroviral therapy (HAART) is recognized as the most effective treatment method for AIDS, and protease inhibitors play a very important role in HAART. The HIV-1 protease molecule has long been used as a drug target and a number of structures exist within the Protein Data Bank of HIV-1 protease bound to an inhibitor molecule.
(a)Locate within the Protein Data Bank (PDB) the 3-D structure of a complex between HIV-1 protease and an inhibitor molecule. State what your chosen entry is, and download the coordinates for the structure to use with a molecular graphics program to investigate your chosen structure.
(b)Using one of the programs rasmol, Jmol or Swiss-PDB Viewer produce an image of the protein that you think clearly illustrates the major structural features within the enzyme and highlights the binding site of the inhibitor molecule. State the commands used within the selected program to obtain your image.
(c)Using tools within the PDB investigate the interactions between the inhibitor and its receptor site. Illustrate with images the different types of interactions that exist and give details of these interactions in your discussion.
(d)Discuss which types of bioinformatics tools and programs could be used to design new potentially improved inhibitors for HIV-1 protease.
There are two forms of glyceraldehyde 3-phosphate dehydrogenase (GAP3DH) expressed in humans. One is expressed ubiquitously and the other expressed in the testis only. In this question you will use protein-protein interaction databases to explore differences in the biochemical function of these two forms.
(a)Use the UniProt to obtain the files for the two human forms of GAP3DH. Carry out an alignment of the protein sequences using NALIGN from the EBI portal. Comment on the similarities and differences in the primary structure of the two forms.
(b)For both forms of GAP3DH use the STRING portal to identify possible protein partners. In each case use the Settings menu to display two shells of interactions, with 10 interacting partners in each shell. Summarise your findings.
(c)Using the information obtained in parts (a) and (b) comment on the functional differences between the two forms of GAP3DH.
Using the E. coli sequence for the cell division protein FtsA (Uniprot reference code P0ABH0) run homology modelling for this sequence using SWISS-MODEL to obtain a 3-dimensional structure for this sequence.
DISCUSS, in detail, the results of the modelling that you obtain, including an in-depth discussion of all of the models obtained, the template used by the program for each model, and all of the key features of the models produced and their quality as shown from the output generated.
Download the pdb coordinates of whichever model you consider to be the best model obtained, and create an image of your modelled structure using rasmol, Jmol or Swiss-PdbViewer which clearly shows the main features of the model.
Micro-RNAs are known to target selected mRNAs and other, non-coding RNAs, as part of their mode of action. In this question you will explore the interaction between an miRNA and the mRNA of ATXN7, a gene implicated in spinocerebellar ataxia type 7.
(a)Retrieve the sequences of human, mouse, dog and cow ATXN7 mRNAs. Align the 3′ UTRs of each set of four mRNAs and identify on your output conserved sequence elements.
(b)Retrieve the file containing the sequence of human miR-124-1 from the miRNA database Run the complete sequence of the miRNA on UNAfold and show the predicted structure of the RNA. Calculate the folding energy per base and comment on your findings.
(c)Using the mature sequence of miR-124-1 (this is given in the miRBase file as miR-124-5p) identify potential binding sites on the 3′ UTR of human ATXN7 mRNAs. Assume that the miRNA will bind to a complementary sequence in the mRNA, but not necessarily with complete complementarity. You will have to use alignment software to map complementary regions. Describe the procedure you followed, discuss the output with reference to a diagram of the alignment.
(d)On the basis of your models how would you expect the miR-124-5p to affect expression of ATXN7 protein.
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