Research Article: Catalytic Water Co-Existing with a Product Peptide in the Active Site of HIV-1 Protease Revealed by X-Ray Structure Analysis

Date Published: November 17, 2009

Publisher: Public Library of Science

Author(s): Vishal Prashar, Subhash Bihani, Amit Das, Jean-Luc Ferrer, Madhusoodan Hosur, Petri Kursula.

Abstract: It is known that HIV-1 protease is an important target for design of antiviral compounds in the treatment of Acquired Immuno Deficiency Syndrome (AIDS). In this context, understanding the catalytic mechanism of the enzyme is of crucial importance as transition state structure directs inhibitor design. Most mechanistic proposals invoke nucleophilic attack on the scissile peptide bond by a water molecule. But such a water molecule coexisting with any ligand in the active site has not been found so far in the crystal structures.

Partial Text: Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS) [1], [2]. Inhibitors of the viral enzyme HIV-1 protease (EC are important components of Highly Active Anti Retroviral Therapy (HAART) for HIV/AIDS [3], [4]. The emergence of mutants of HIV-1 protease resistant to inhibitor action necessitates continuous improvement of existing drugs and also of design of new inhibitors. Understanding the catalytic mechanism and the structure and interactions of the transition state would contribute significantly in the development of novel inhibitors. Based on computational [5]–[8], biochemical [9]–[11] and structural results [12]–[16], two types of proposals have been made in the past for the catalytic mechanism: direct and indirect [reviewed in 17]–[18]. In the direct type, championed mostly by computational studies, the nucleophilic attack on the carbonyl carbon atom of the scissile peptide bond is directly by carboxyl oxygen atom of the catalytic aspartates. In the indirect type, the attack is by a water molecule [19]. The position and hydrogen bonding patterns from this water molecule at the time of attack are different in different proposals of the catalytic mechanism, and therefore knowing the location and interactions of nucleophilic water molecule would be a step in establishing the correct mechanism for this enzyme.



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