Acquired Immune Deficiency Syndrome AIDS

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AIDS is the bubonic plague of the late-twentieth and twenty-first centuries. At the end of 2003, an estimated 40 million people worldwide were infected with the human immunodeficiency virus (HIV); AIDS is estimated to have taken 20 million lives, and an estimated 5 million people contract the disease annually.34 At the early stage of the HIV virus life cycle, the protein of the virus exists as a single polypeptide chain. As the virus develops, the enzyme HIV-1 protease is responsible for cutting the chain into segments that will mature and infect new cells. Disrupting this event prevents the virus from reproducing. Structure studies have revealed the detailed mechanism by which the enzyme excises the protein and have provided the key for designing inhibitors that bind more tightly to the enzyme than the protein chain they are charged with cutting.

The earliest HIV-related crystal structures found in the PDB were published in the early 1990s: a complex between a synthetic protease of HIV-1 and a substrate-based hydroxyethylamine inhibitor (7HVP)35 and an HIV protease complex with L-700,417 (4PHV).36The first NMR structure of an HIV zinc finger-like domain was published in 1990 (2ZNF).37 Only 16 years later, an HIV keyword search of the PDB returns almost 400 structures, including several genetic strains of the enzyme, complexes of the enzyme with many different drugs and inhibitors, and dozens of mutant enzymes. Hundreds more are most likely stored in the proprietary databases of pharmaceutical companies, where they are used to test and refine new drug candidates.

At least six protease inhibitors that attack HIV-1 have already been approved to treat people infected with the virus, and several others are in late stages of clinical development. Structures of all six drugs currently in clinical use are available in complexes in the PDB: indinavir, which is also discussed below (1HSG),38 saquinavir (1HXB),39 ritonavir (1HXW),40 nelfinavir (1OHR), amprenavir (1T7J), and Kaletra, which is a combination of lopinavir (1MUI) and ritonavir.

The details of how inhibition of HIV protease may take place is highlighted by the structure of the complex of HIV-1 protease and indinavir (1HSG),38 marketed today under the tradename Crixivan as part of the so-called protease cocktail treatment. The interaction of the inhibitor and the protein is shown in Figure 4b using the Ligand Explorer software. Highlighted is the critical hydrogen-bonding interaction of the hydroxyaminepentane amide moiety interacting with the hydroxyl groups of the critical ASP 25 carboxyl groups from both of the polypeptide chains of this symmetric protein. Ligand Viewer can be used to explore all the hydrophilic and hydrophobic interactions between this viral inhibitor and the virus protease. Additional information on the structures of HIV protease can be found in the HIV-1 Protease Protein Structures Database.

3.17.4.2 Diabetes

Insulin is a hormone that carries messages describing the amount of sugar that is available in the blood at any one time. It is synthesized in the pancreas in response to food intake. It then informs liver, muscle, and fat cells to take glucose from the blood and store it for subsequent use. Insufficient production of insulin causes glucose levels to rise in the blood, leading to the disease diabetes mellitus. Diabetes is most often found in adults, but it can occur in children as well, and it is one of the major chronic diseases of the modern world. Early treatment of diabetes consisted of injections of insulin from either pigs or cows. Now the insulin given is produced using recombinant methods.

Insulin has historically been much studied, since it is a small protein that proved to be relatively easy to isolate from natural sources, such as from pig and beef pancreases. Dorothy Hodgkin took the first x-ray diffraction photographs of insulin in 1935. The structure was not solved until 34 years later, when the structure of 2-Zn insulin was reported by Hodgkin and her co-workers in August 1969. She was awarded the 1964 Nobel Prize in Chemistry for her work on insulin. The earliest insulin structure that can be found in the PDB is that of 4-Zn insulin, published in Nature by Hodgkin etal. in 1976 - 1ZNI. Since that time, almost 200 structures of insulin or closely related molecules have been deposited in the PDB archives. Approximately one-quarter of these structures were studied using NMR techniques.

The structure of insulin shown in Figure 6, taken from the RCSB PDB Molecule of the Month feature, illustrates that there is only a single amino acid difference between pig46 and human47 insulin - a threonine in human at the end of the chain is replaced by alanine in pig. Its surface location as revealed by the structure and the conserved chemical nature of the substitution reveals details of how insulin binds to the appropriate cell receptor.

3.17.4.3 The Common Cold

A cure for the common cold is still illusive, but there are moderately effective treatments that attack the problem indirectly. The rhinovirus responsible for the common cold is the heart of the problem in the majority of cases. Currently, there are more than 75 structures of rhinovirus in the PDB. The structure of the virus itself, HRV1A (1R1A),48 complexed with various antiviral ligands,49'50 and ligand binding in drug-resistant mutants51 have been published. For a review of this work, see the article by Bella and Rossmann.52

While we now understand the basic structure of the protein viral capsid, we have been unable to find a lasting cure, since the virus continues to evolve. The basic action of the rhinovirus is similar to that of HIV, but less deadly for most. The virus attaches itself to the cell surface, and its RNA enters the human cell, which then directs the cell to replicate the virus. Unlike HIV, which focuses on the immune system, rhinoviruses mainly attack the respiratory tract. Figure 7 illustrates one such capsid of the rhinovirus. The capsid itself is made up of 60 individual building blocks arranged in an icosohedral arrangement. Figure 7a53 illustrates a rhinovirus bound to a receptor protein on the cell surface, shown in blue. In Figure 7b,54 antibodies against the infection can attach themselves to the virus in the same position to prevent the virus from binding to the cell surface and causing infection. Work toward finding pharmaceutical agents effective against the common cold continues.

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