Seminars Archive

Structural-functional studies on two proteases: Human Immunodeficiency Virus type 1 Protease (HIV1PR) and Human Insulin Degrading Enzyme (IDE) and Amyloid beta (Aβ) clearance.

Abstract
The human immunodeficiency virus 1 (HIV-1) protease (PR) is an aspartyl protease essential for HIV-1 viral infectivity and is already a target of several anti-AIDS therapies. Despite more than twenty years of research, the catalytic mechanism for the cleavage of the peptide bond catalyzed by aspartyl proteases is still debated. We chemically synthesized a fully active HIV-1 PR using modern chemical-ligation methods and solved the crystal structures of two complexes with classic substrate-derived inhibitors at 1.04- and 1.2-Å resolution, respectively. We then used the atomic resolution crystal structures for classical molecular dynamic simulations, and found putative catalytically competent reactant states for both the so far debated catalytic mechanisms (lytic water and direct nucleophilic attack). Alzheimer\'s disease is associated with deposition of amyloid beta (Aβ) peptide in the brain. Insulin degrading enzyme (IDE) is one of the proteases involved in the clearance of Aβ, and our recent structural analyses revealed the first molecular details of this peptidase. A big catalytic chamber selectively encapsulates and cleaves amyloidogenic peptides such as Aβ, insulin and amylin. Substrate selectivity is determined by several factors such as size and charge distribution of the catalytic chamber and conformational flexibility of both IDE and its substrates. Structural and biochemical insights into IDE provide potential therapeutic strategies for the control of Aβ clearance.