The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor

TLDR

SARS‑CoV is the etiologic agent of the SARS outbreak, and its main protease (33.8 kDa) is essential for viral replication by processing the pp1a and pp1ab polyproteins. The study aimed to determine the crystal structures of the SARS‑CoV main protease at different pH values and in complex with a specific inhibitor. X‑ray crystallography was employed to solve the protease structures at multiple pH levels and with the inhibitor bound, revealing pH‑dependent conformational changes. The resulting structures show an augmented serine‑protease fold with a Cys‑His catalytic dyad, unexpected inhibitor‑binding mode, and provide a structural basis for rational drug design.

Abstract

A newly identified severe acute respiratory syndrome coronavirus (SARS-CoV), is the etiological agent responsible for the outbreak of SARS. The SARS-CoV main protease, which is a 33.8-kDa protease (also called the 3C-like protease), plays a pivotal role in mediating viral replication and transcription functions through extensive proteolytic processing of two replicase polyproteins, pp1a (486 kDa) and pp1ab (790 kDa). Here, we report the crystal structures of the SARS-CoV main protease at different pH values and in complex with a specific inhibitor. The protease structure has a fold that can be described as an augmented serine-protease, but with a Cys-His at the active site. This series of crystal structures, which is the first, to our knowledge, of any protein from the SARS virus, reveal substantial pH-dependent conformational changes, and an unexpected mode of inhibitor binding, providing a structural basis for rational drug design.