Protein family review
This in an extract of a protein family review which first appeared in GenomeBiology, and is reproduced by permission of the publisher, BioMedCentral Ltd.
Authors:
1Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, USA
2Department of Pathology and Experimental Medicine, University of Florida, Gainesville, FL 32610, USA
3Macromolecular Crystallography Laboratory, National Cancer Institute, Frederick, MD 21702, USA
Correspondence:
Ben M Dunn.
Email:
bdunn@college.med.ufl.edu
Read the full article
Subscribers to GenomeBiology may view the full version of this review article online at http://genomebiology.com/2002/3/4/reviews/3006
Published:
26 March 2002
Retroviral proteases
Summary
The proteases of retroviruses, such as leukemia viruses, immunodeficiency viruses (including the human immunodeficiency virus, HIV), infectious anemia viruses, and mammary tumor viruses, form a family with the proteases encoded by several retrotransposons in Drosophila and yeast and endogenous viral sequences in primates. Retroviral proteases are key enzymes in viral propagation and are initially synthesized with other viral proteins as polyprotein precursors that are subsequently cleaved by the viral protease activity at specific sites to produce mature, functional units. Active retroviral proteases are homodimers, with each dimer structurally related to the larger class of single-chain aspartic peptidases. Each monomer has four structural elements: two distinct hairpin loops, a wide loop containing the catalytic aspartic acid and an α helix. Retroviral gene sequences can vary between infected individuals, and mutations affecting the binding cleft of the protease or the substrate cleavage sites can alter the response of the virus to therapeutic drugs. The need to develop new drugs against HIV will continue to be, to a large extent, the driving force behind further characterization of retroviral proteases.
Frontiers
Understanding protease function in polyprotein processing and viral replication remains important. Despite the early successes with the development of drugs that control HIV infection by blocking proteolytic processing, the poor bioavailability of inhibitors in vivo leads to suboptimal drug levels. The high turnover of the virus (two or three cycles of replication per day) coupled with the high viral load in infected individuals, and the mutation rate has led to the emergence of viruses resistant to all approved drugs [17]. The variant forms of drug-resistant protease have been expressed and studied biochemically and structurally, and a new round of drug design is underway to target variant forms. One can imagine that this cycle will continue until a universal inhibitor is found that binds tightly to all forms of the viral enzyme. Other approaches, such as the development of peptides that bind to the dimerization interface and block assembly of functional proteases, are also under extensive investigation.
© BioMedCentral Ltd. Protein family reviews appear as regular features in GenomeBiology. A complete list of protein family reviews is available online at http://genomebiology.com/proteinfamilyreviews/
HIV-1 protease sequences are heterogeneous 
The 'fireman's grip', a stereotypical rigid network structure involving the Asp-Thr-Gly signature sequence in (a) the classical aspartic peptidases and (b) the retroviral proteases