The Dynamic Binding Site of HIV Integrase
Julie Schames and I in the group of Andy McCammon, discovered a new part of the binding site of the HIV integrase, an enzyme which inserts the viral DNA into the host DNA . This extra binding site explained the mutagenesis data of scientists at Merck (NSF news story, SDSC news story, AutoDock) and helped lead to the development of the first FDA-approved integrase inhibitor, raltegravir (Isentress). This billion dollar drug is now a mainstream treatment of AIDS.
A molecular dynamics simulation of the Shionogi inhibitor bound to integrase induced the opening up of the newly observed "trench" (hover over the figure on the right). This we detected by using the "relaxed-complex method" in which the Shionogi inhibitor was docked to multiple snapshots of the protein during the simulation. The first image shows the inhibitor in the x-ray crystal position used at the start of the simulation. The second image is the inhibitor docked in two additional positions from a simulated structure. The trench is the position to the right. A comparison of the two structures makes clear how flexible is the active site.