Subject Code : BE6056
Assignment Task:

Task:

Q1
Protein kinase inhibitors are important drugs as they block the action of the protein kinase and their ability to catalyse phosphorylation reactions. The process of phosphorylation regulates many biological processes, and protein kinase inhibitors can be used to treat diseases which result from hyperactive protein kinases (including mutant or overexpressed kinases in cancer) or to modulate cell functions to overcome other disease drivers.

(a) Locate within the Protein Data Bank (PDB) the 3-D structure of a complex between a protein kinase 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, Chimera 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 that were discussed in Lecture 7 investigate the interactions between the inhibitor and its receptor site (Ligand Interaction). 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 protein kinase.

20 marks

Q2

Cytochrome P450s are a family of proteins involved in phase I drug metabolism reactions. They are highly expressed in the liver, in the endoplasmic reticulum membrane. In this question you will explore the use of protein-protein interaction databases to find out what other proteins P450s interact with and whether the potential partnerships could have biological significance.

(a) Use the UniProt file for human cytochrome P450 3A4 as your starting point. Summarise the key structural features of P450 3A4 including how it is able to bind to the ER membrane, and structural features of the active site.
(b) Use a range, at least four, of PPI databases to identify possible protein partners. Summarise your findings.

(c) From your searches select three proteins with different activities that interact with P450 3A4, describe the evidence for the interaction and discuss whether these interactions could be relevant to P450’s ability to metabolise drugs. Wherever possible select proteins for which there is experimental evidence for the interaction.

25 marks

Q3
Using the H. sapiens sequence for the beta-adrenergic receptor kinase 2 (Uniprot reference code P35626) 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, Chimera or Swiss-PdbViewer which clearly shows the main features of the model.

25 marks

Q4
RNA viruses have regions at the 5& and 3 end of the genome which have a regulatory function. These are usually short (a few hundred bases) and have a high tendency to form folded structures.

The 5&; UTR of SARS-CoV-2 was discussed in Lecture 8 and Tutorial 7. You also had the opportunity to explore databases of viral sequences in Tutorial 10.

 Retrieve the sequences of the seven variants of coronavirus known to infect humans, and from them create a single FASTA file containing the 5& UTR up to and including the first 50 bases after the initiation codon of the first open reading frame (referred to as 5' UTR_AUG_+50). The seven types are listed at https://www.cdc.gov/coronavirus/types.html

 Run an alignment of the seven UTR_AUG_+50 sequences to find out whether there are regions of homology in the seven UTRs. Show the output of the alignment and discuss the results.

 Using a local folding approach, as described in Lecture 6 for the 3' UTR of IL-2 mRNA, map the key structural elements of the 5' UTR_AUG_+50 comparing SARS-CoV and SARS-CoV-2 only. How do they compare?

 One of the structural elements in the SARS-CoV-2 LTR includes the initiation codon of the first open reading frame. Is the codon likely to be translated by a scanning mechanism (discussed in Tutorial 6)? Discuss how this may, or may not, be possible.

 

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  • Posted on : January 23rd, 2019

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