Final Problems - 2009SPRING

Final Problems - 2009SPRING - Name_ Final Exam MCB C100A /...

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Name____________________ Final Exam MCB C100A / Chem C130 Spring 2009 11 pages total including cover 1 _____ 2 _____ 3 _____ 4 _____ 5 _____ 6 _____ 7 _____ 8 _____ 9 _____ 10 _____ total _____
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1a). Below is the structure of oseltamivir, an antiviral drug marketed as Tamiflu™. Tamiflu is effective against the recently emerged H1N1 influenza strain. The compound is an orally bioavailable “prodrug” that is hydrolyzed in vivo to the carboxylate. Is Tamiflu™ a nucleoside analogue and if so, what base does it mimic ? ( Explain briefly ) ( 5 pts. ) 1b). If a mutation weakens drug binding by 11.7 kJ/mole at 37 C, calculate the ratio of dissociation constants of drug for the mutant and wild type enzymes at 37 C. ( 5 pts. ) 1c) . Using 1b), how much higher concentration of the drug in blood would be required to inhibit the mutant enzyme to the same degree as the normal dose inhibits the wild-type protein? ( 5 pts. ) 1d). The enzyme to which Tamiflu binds has a molecular weight of 50 kD. What approach would you use to determine structural details of the binding site around the drug molecule? ( 5 pts. )
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1f. The target of Tamiflu is a viral enzyme of ~450 acids. In different influenza isolates, the length of the protein can vary by over 20 amino acids. In what part of the structure do you think the insertions and deletions are most likely to occur ? Briefly justify your answer. ( 5 pts. ) 1g. Suppose you are investigating a Tamiflu-resistant strain isolated from a student at Malcolm X Elementary School in Berkeley. Compared to the closest related drug-sensitive strain in your collection, you discover 26 changes in the nucleotide sequence of the gene but only 10 changes in the amino acid sequence of the target protein. Briefly explain why there could be more changes in the gene sequence than the protein sequence. ( 5 pts. ) 1h. Do you think the ten amino-acid substitutions in the Tamiflu-resistant target are likely to change the fold of the protein? Why or why not? ( 5 pts. ) 1i. A key question to answer in order to understand the mechanism of drug resistance is to define which sequence changes weaken drug binding. Propose a computational method you would use analyze the sequence of the mutant target protein to identify which of the 10 substitutions are most likely to weaken drug binding. Using this method, what characteristic (result) would be likely to identify the residues that confer resistance and why? Hint: There are many sequences of different flu isolates available. ( 5 pts. )
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2. True/false. ( 2 pts. each ) 2a. Loops in proteins are characterized by different main-chain dihedral angles than secondary structures.
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This note was uploaded on 01/27/2011 for the course MCB 100A taught by Professor Kuryian during the Spring '09 term at University of California, Berkeley.

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Final Problems - 2009SPRING - Name_ Final Exam MCB C100A /...

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