Topography of a 2.0 angstrom structure of alpha(1)-antitrypsin reveals targets for rational drug design to prevent conformational disease

Members of the serpin family of serine proteinase inhibitors play important roles in the inflammatory, coagulation, fibrinolytic, and complement casca des. An inherent part of their function is the ability to undergo a structu ral rearrangement, the stressed (S) to relaxed (R) transition, in which an extra strand is inserted into the central A beta-sheet. In order for this t ransition to take place, the A sheet has to be unusually flexible. Malfunct ions in this flexibility can lead to aberrant protein linkage, serpin inact ivation, and diseases as diverse as cirrhosis, thrombosis, angioedema, emph ysema, and dementia. The development of agents that control this conformati onal rearrangement requires a high resolution structure of an active serpin . We present here the topology of the archetypal serpin alpha(1)-antitrypsi n to 2 Angstrom resolution. This structure allows us to define five cavitie s that are potential targets for rational drug design to develop agents tha t will prevent conformational transitions and ameliorate the associated dis ease.