The proteins that comprise the human immunodeficiency virus (HIV) are produced in the form of long "polyproteins." These polyproteins must be cleaved to yield the active protein components of the mature virus. The HIV-1 protease is a novel aspartic protease that functions to cleave the nascent polyproteins during viral replication. When viewed as a space-filling model, the novel structural features of this enzyme are not readily apparent. However, a ribbon structure quickly reveals the dimeric natureof this protein. Each monomer subunit contains two twisted beta sheets and a small alpha helix. The HIV-1 protease consists of two identical polypeptides of 99 amino acids, each chain having an N-terminal Pro and C-terminal Phe. The active site cleft is "covered" by flaps that extend from Met-46 to Lys-55. Catalysis of protein chain cleavage by this protease is mediated by twin Asp-25 residues juxtaposed in the active site. These two aspartates are said to form a "catalytic dyad". One of these carboxyl groups exhibits an unusually low pKa of 3.3 and the other displays an unusually high pKa of 5.3. This catalytic dyad of aspartate residues normally interacts with the amide bond to be cleaved in the polypeptide substrate. In the structure shown here, Crixivan, the new AIDS drug, made by Merck, has replaced the substrate, inhibiting the protease. Crixivan and the other new AIDS drugs, known as "protease inhibitors" elicit highly specific inhibition of the HIV protease. These drugs must also be able to easily cross the cell membrane, so that therapeutically effective concentrations of the drug can be delivered to diseased cells. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule.
The HIV-1 protease consists of two identical polypeptides of 99 amino acids, each chain having an N-terminal Pro and C-terminal Phe. The active site cleft is "covered" by flaps that extend from Met-46 to Lys-55. Catalysis of protein chain cleavage by this protease is mediated by twin Asp-25 residues juxtaposed in the active site. These two aspartates are said to form a "catalytic dyad". One of these carboxyl groups exhibits an unusually low pKa of 3.3 and the other displays an unusually high pKa of 5.3. This catalytic dyad of aspartate residues normally interacts with the amide bond to be cleaved in the polypeptide substrate. In the structure shown here, Crixivan, the new AIDS drug, made by Merck, has replaced the substrate, inhibiting the protease. Crixivan and the other new AIDS drugs, known as "protease inhibitors" elicit highly specific inhibition of the HIV protease. These drugs must also be able to easily cross the cell membrane, so that therapeutically effective concentrations of the drug can be delivered to diseased cells. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule.
Catalysis of protein chain cleavage by this protease is mediated by twin Asp-25 residues juxtaposed in the active site. These two aspartates are said to form a "catalytic dyad". One of these carboxyl groups exhibits an unusually low pKa of 3.3 and the other displays an unusually high pKa of 5.3. This catalytic dyad of aspartate residues normally interacts with the amide bond to be cleaved in the polypeptide substrate. In the structure shown here, Crixivan, the new AIDS drug, made by Merck, has replaced the substrate, inhibiting the protease. Crixivan and the other new AIDS drugs, known as "protease inhibitors" elicit highly specific inhibition of the HIV protease. These drugs must also be able to easily cross the cell membrane, so that therapeutically effective concentrations of the drug can be delivered to diseased cells. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule.
This catalytic dyad of aspartate residues normally interacts with the amide bond to be cleaved in the polypeptide substrate.
In the structure shown here, Crixivan, the new AIDS drug, made by Merck, has replaced the substrate, inhibiting the protease. Crixivan and the other new AIDS drugs, known as "protease inhibitors" elicit highly specific inhibition of the HIV protease. These drugs must also be able to easily cross the cell membrane, so that therapeutically effective concentrations of the drug can be delivered to diseased cells.
You may wish to manipulate this image yourself: