LS1a_F08_Lecture_notes 11-20-2

LS1a_F08_Lecture_notes 11-20-2 - 1 Discovery of HIV...

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Unformatted text preview: 1 Discovery of HIV protease In the mid-1980s it was discovered that mutations in the RNA sequence that we now know to encode the HIV protease protein resulted in defective HIV particles that could not infect cells. Moreover, these noninfectious HIV particles contained unprocessed Gag and Gag-Pro-Pol polyproteins rather than the shorter, mature proteins. Because the use of a protease enzyme to cleave proteins into smaller products is a common theme in nature, scientists speculated that one of the proteins encoded by the HIV genome was a viral protease responsible for processing of the Gag and Gag-Pro-Pol polyproteins. A breakthrough in our understanding of HIV protease came from comparing the sequences of regions of the HIV genome (whose complete sequence was published in 1985) with the DNA sequences encoding known proteases. Scientists realized that one of the genes in HIV the gene encoding PR, or HIV protease was similar, or homologous , to genes known to encode a class of proteases called aspartyl proteases. For example, a key sequence signature of aspartyl proteases is the Asp-Thr/Ser-Gly tripeptide. All aspartyl proteases contain this sequence of three amino acids: aspartic acid, followed by either threonine or serine, followed by glycine. (Note, however, that the the converse is not necessarily true the mere presence of these three consecutive amino acids in a protein does not necessarily mean that the protein is an aspartyl protease). The ~100-amino acid sequence of HIV protease indeed contained this signature sequence, as well as several other sequence hallmarks of aspartyl proteases. We will learn the crucial chemical role of this aspartic acid residue shortly. Two other observations confirmed that HIV protease is a member of the aspartyl protease family: (i) HIV protease is inhibited by known aspartyl protease inhibitors such as pepstatin, a natural peptide; and (ii) the three-dimensional structure of HIV protease is similar to that of other aspartyl proteases. 2 Overview of the three-dimensional structure of HIV protease One of the earliest solved three-dimensional structures of a retrovirus protein was the structure of HIV protease, published in 1989. The ingenious ways in which scientists can solve the molecular structures of macromolecules is commonly the subject of an entire course, and will not be described here. For now, simply recall how Dan told you that the amino acid sequence of a protein determines its three- dimensional structure. In the case of HIV protease, this three-dimensional structure has been solved with sufficient precision to deduce the relative location of most atoms of the protein. The functional properties of HIV protease, including its ability to catalyze the cleavage of a protein, are determined by its three- dimensional structure yet another reminder that molecular structure determines function. HIV protease is a dimer , a complex containing two identical HIV protease molecules noncovalently associated (indicated...
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LS1a_F08_Lecture_notes 11-20-2 - 1 Discovery of HIV...

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