Crystallography allows the elucidation of protein’s structure and mechanism of action at a molecular level. One example of such studies is our work on structures of RNases H and in particular their complexes with the substrate RNA/DNA. RNase H - a small nuclease that cleaves the RNA strand of RNA/DNA hybrids is an example of an important drug target – it is the only enzymatic activity encoded by the HIV for which no specific inhibitor is available. In the second part of the talk I will discuss how structural information about proteins that are drug targets can be used to improve existing inhibitors or activators or even attempt to design novel ones using computational methods. One such example is the development of antiviral drug Tamiflu. Another important application of crystallography in drug design is a so-called ‘fragment-based design’. Computational docking is first used to identify small compounds that could potentially interact with a selected region of the protein surface. Protein crystals are then soaked with these compounds (usually several hundred in total) and the protein structure is solved. Compounds that interact with the protein are observed in the resulting electron density maps and can be identified by their shape. Even weak interactors can be identified and several compounds binding in one region can be combined to produce a tightly binding and specific inhibitor.

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