Sandbox Reserved 955

Description

Proteases are one of the 3 (along with reverse transcriptases and integrases) virally encoded enzymes necessary for replication of immunodeffiency virus 1 ^[1] (HIV-1). The protease is a member of the asparctic protease which cleaves the gag and pol polyproptein from the early life cycle of the virus. This cleavage is essential for the virus maturation to form functionnal small-sized proteins so that it can infect other cells. Without these proteases the virus cannot be infective. The enzyme is a dimer composed of two identical subunits forming a tunnel with the active site inside The mechanism of polypeptides cleavage uses a water molecule as a nucleophile simultaneously with a well-placed asparctic acid acid for hydrolysis of the scissile peptide bond. The structure of HIV-1 protease with protein bound can't be solved as it would be cleaved before, we analyse how inhibitors bind to the active site to solve the structure Inhibitors like the hydroxyethylamine bind to the active site mimicking the tetrahedral transition state of the proteolytic reaction ^[2]. The inhibitor interacts with the active site by direct hydrogen bonds and indirect hydrogen bonds through water molecules.

Structure

Biological and Biotechnological Relevance

HIV-1 protease has a crucial importance in drug design as inhbition of it makes the virus noninfective. It prevents formation of mature protein of the HIV virus. The most encouraging inhibtors are the hydroxyethylamine substrate-based inhibitors which led to the discovery of the first protease inhibitor, saquinavir. But mutations coding for alteration of the active site conformation facilitates resistance to protease inhibitors. Structure comprehension of HIV protease through structural analysis is crucial to design inhibitors to slow down worldwide AIDS spreading epidemic.