SARS Coronavirus Main Proteinase

From Proteopedia

Coronaviruses

Coronaviruses are enveloped, positive-sense RNA viruses and are the second most prevalent cause of the common cold (rhinoviruses are the first). These viruses have the longest non-segmented RNA genomes currently known, ranging from 27 to 31 kb. Translation of the genome occurs in two phases: (1) the early phase were the viral replicase complex is assembled, and (2) the late phase, structural and nonstructural proteins are translated from a negative-sense RNA template. The maturation of the RNA polymerase is achieved through extensive proteolytic processing by three cysteine peptidases. Two are papain-like proteases (PL^pro) and the third is the main protease, also known as the 3C-like protease (3Cl^pro).

SARS

The highly infectious severe acute respiratory syndrome (SARS) has caused one near pandemic to date, between the months of November 2002 and July 2003, with 8,096 known cases and 774 confirmed deaths (a fatality rate of nearly 10%). Genetic comparisons revealed this virus as a completely new coronavirus. According to the World Health Organization's (WHO) April 2004 concluding report, China had the vast majority of cases, but Taiwan, Singapore, and Canada also had cases in the hundreds. The virus spread to 37 countries, but the Global Alert and Response system as well as drastic action taken by the Chinese government effectively limited the spread of the disease. It has been established that the SARS virus can infect birds, livestock, and pets; however, the exact reservoir and range of host species is, at this point, unknown and SARS has the potential to reemerge at an unknown time.

The SARS Main Protease

The SARS main protease, M^pro, is a 33.8 kDA belonging to the cysteine protease family. As in all coronaviruses, except infectious bronchitis virus (IBV), the enzyme is a homodimer. It has been established that dimerization is essential for catalytic activity because the N-finger of one subunit is involved in organizing the substrate binding-pocket of the other. The catalytic dyad is composed of Histidine 41 and Cysteine 145. From the pH dependency of enzymatic activity, the pKa's have been determined as 6.4 for the histidine and 8.3 for the cysteine. Development of broad spectrum antivirals for coronaviruses is highly desirable as several new species have been recently discovered and the coronaviruses tend to have a wide host range. Thus the highly conserved M^pro is an ideal target for viral inhibition.

Each monomer of the SARS M^pro consists of three domains. The active site is located at the connection between the first domain (residues 1-101) and second domain (residues 102-184)

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