Bi1_2011_PS5_v2_solution

Bi1_2011_PS5_v2_solution - Bi1 The Biology and Biophysics...

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Bi1: The Biology and Biophysics of Viruses Spring 2011 Problem Set 5: Flu Virus and HIV Due Tuesday, May 10 at 4:00 P.M. in the Bi 1 closet Name: ANSWER KEY ___________________________________________________ Section # : ___________________________________________________________ Mail Code : ___________________________________________________________ TA Names : ___________________________________________________________ Date and Time turned in : _______________________________________________ Number of pages including this one : _____________________________________ AFTER YOU FINISH: How long did it take you to complete this problem set? ____________________________ Go to the Bi1 moodle site at http://courses.caltech.edu/ and take the homework survey There are 2 questions. The number of parts to each question is listed at the beginning of each; be sure to answer all the parts! Grade: Problem 1 __________ Problem 2 __________ TOTAL: _________ HOMEWORK INSTRUCTIONS 1) Turn in your homework stapled to this cover page. 2) Use separate sheets of paper for your answers. 3) Write or type your answers neatly. 4) Put your name on each page of your answers. 5) Box your answers, please, so that the grader can find them. Points may be deducted if you don’t follow these instructions!
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Page 2 of 15 Problem 1: Drug design for the influenza virus (50 points 3 parts) Suggested Readings: Enzymes and amino acids Freeman pp. 46-48, 58-62 Viruses Freeman pp. 769-782, Lecture 17 Neuraminidase is an influenza glycoprotein that cleaves sialic acids on host cell glycoproteins. (To avoid confusion, sialic acid is a monosaccharide, NOT an amino acid. Post-translational modifications add sialic acids to carbohydrates on proteins.) Since neuraminidase function is critical for the propagation of influenza virus, neuraminidase inhibition has been intensely studied and has resulted in several drugs, including Tamiflu (oseltamivir) and Relenza (zanamivir). Common strains of influenza have become resistant to Tamiflu but not to Relenza, which raises the question of what might make one inhibitory drug more effective than another. Here, you will think about some key aspects of this question. (Please keep your answers simple and short, no more than the max length for each part.) A. Structural Analysis: Go to http://www.proteopedia.org/wiki/index.php/Avian_Influenza_Neuraminidase%2C_Tamiflu_and _Relenza . Scroll down to the section “Neuraminidase Structure and Conserved Amino Acids” and look at features of the neuraminidase structure by clicking on the green links. i. (2 points) Why does influenza virus require neuraminidase activity? (2 sentences max) Hemagglutinin, another influenza protein, is critical for enabling influenza to bind to an uninfected host cell, but it also keeps newly-made influenza bound to the host cell which has already been infected, so to free these newly-made viral particles, neuraminidase cleaves sialic acid. This is critical for the propagation of the virus. ii. (4 points) In this structure, the neuraminidase protein was crystallized with Tamiflu bound to the sialic acid binding pocket. What might this imply about how Tamiflu inhibits neuraminidase activity? Why might it be difficult to crystallize neuraminidase with bound sialic acid? (3 sentences max) Neuraminidase cleaves sialic acid and releases it after cleavage, making it difficult to crystallize neuraminidase with bound (and uncleaved) sialic acid. Tamiflu, however,
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