PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons
E-Collection

Related Articles
Protein Folding and Misfolding: It's the Journey, Not the Destination
March 2015
CCR5 and HIV Infection
January 2015
HIV/AIDS: Pre-fusion Env Exposed
January 2015
HIV/AIDS: Slide to Enter
January 2015
Updating ModBase
January 2015
Power in Numbers
August 2014
Quorum Sensing: A Groovy New Component
August 2014
Bacterial CDI Toxins
June 2014
Immunity: One Antibody to Rule Them All
June 2014
Virology: A Bat Influenza Hemagglutinin
March 2014
Virology: Making Sensitive Magic
March 2014
Virology: Visualizing Cyanophage Assembly
March 2014
Virology: Zeroing in on HBV Egress
March 2014
Viroporins
March 2014
Cas4 Nuclease and Bacterial Immunity
February 2014
Microbial Pathogenesis: A GNAT from Pseudomonas
February 2014
Microbial Pathogenesis: Targeting Drug Resistance in Mycobacterium tuberculosis
February 2014
Microbiome: The Dynamics of Infection
September 2013
Membrane Proteome: A Funnel-like Viroporin
August 2013
Infectious Diseases: A Pathogen Ubiquitin Ligase
May 2013
Infectious Diseases: A Shared Syringe
May 2013
Infectious Diseases: Determining the Essential Structome
May 2013
Infectious Diseases: Targeting Meningitis
May 2013
NDM-1 and Antibiotics
May 2013
Bacterial Hemophores
January 2013
Microbial Pathogenesis: Computational Epitope Prediction
January 2013
Microbial Pathogenesis: Influenza Inhibitor Screen
January 2013
Microbial Pathogenesis: Measles Virus Attachment
January 2013
Microbial Pathogenesis: NEAT Iron
January 2013
Membrane Proteome: Sphingolipid Synthesis Selectivity
December 2012
A signal sensing switch
September 2012
Gauging needle structure
July 2012
Anthrax Stealth Siderophores
June 2012
A Pseudomonas L-serine dehydrogenase
May 2012
Pilus Assembly Protein TadZ
April 2012
Making Lipopolysaccharide
January 2012
Superbugs and Antibiotic Resistance
December 2011
A change to resistance
November 2011
An effective and cooperative dimer
November 2011
The Perils of Protein Secretion
November 2011
Bacterial Armor
October 2011
Breaking down the defenses
September 2011
Moving some metal
August 2011
Capsid assembly in motion
April 2011
Know thy enemy … structurally
October 2010
Treating sleeping sickness
May 2010
Bacterial spore kinase
April 2010
Hemolysin BL
January 2010
Unusual cell division
October 2009
Anthrax evasion tactics
September 2009
Toxin-antitoxin VapBC-5
September 2009
Antibiotic target
August 2009
Lysostaphin
July 2009
Tackling influenza
June 2009
You look familiar: the Type VI secretion system
June 2009
Unique SARS
April 2009
Anthrax stealth molecule
March 2009
A new class of bacterial E3 ubiquitination enzymes
January 2009
Antiviral evasion
October 2008
SARS connections
September 2008
SARS Coronavirus Nonstructural Protein 1
June 2008

Research Themes Infectious diseases

SARS Coronavirus Nonstructural Protein 1

PSI-SGKB [doi:10.3942/psi_sgkb/fm_2008_6]
Featured System - June 2008
Short description: Researchers at the Joint Center for Structural Genomics have obtained the first look at nsp1 (nonstructural protein 1), a major factor in the pathogenicity of the coronavirus that causes SARS (severe acute respiratory syndrome).

Researchers at the Joint Center for Structural Genomics have obtained the first look at nsp1 (nonstructural protein 1), a major factor in the pathogenicity of the coronavirus that causes SARS (severe acute respiratory syndrome). Ever since the international outbreak of the virus in 2003, researchers have been studying this virus, hoping to find methods to fight it if it reemerges in the future. Nsp1 may play an important part in this fight.

The Coronavirus Proteome

The genome of the SARS coronavirus encodes 28 proteins that orchestrate its lifecycle of cell death. Four of these are structural proteins on the surface of the virus, sixteen are nonstructural proteins involved in replication (named nsp1-nsp16), and the rest are a loose collection of "accessory" proteins. Some of the nonstructural proteins have familiar functions common to many viruses, such as a polymerase that replicates the RNA genome and proteases that cleave the viral polyproteins into functional pieces. Others, including nsp1, play supporting roles by suppressing the normal processes of the cell and blocking the normal defenses. Nsp1 is an attractive target for therapy since it plays a role early in infection: it is one of the first proteins produced by the virus and it has been shown to be important for the pathogenicity of the virus.

The Fight Against SARS

By studying viruses that are missing nsp1, researchers now think that nsp1 blocks the normal innate immune response that protects us from viral infection. This allows the SARS coronavirus to infect cells and replicate, free from our normal defenses. Recently, however, researchers have used this knowledge to fight back. They have designed a vaccine by engineering a coronavirus that is missing nsp1. This mutant coronavirus is weakened, much like the attenuated polioviruses used in the polio vaccine, allowing them to stimulate the immune response without leading to a full infection of SARS.

A New Fold

The structure of nsp1 (pdb entry 2hsx) yielded another dividend: a new fold. Nsp1 is a small protein with 179 amino acids. Both ends of the chain are disordered, but the center (residues 13 to 128) form a stable folded structure. The NMR structure obtained by JCSG reveals an entirely new fold composed of an irregular six-stranded beta barrel with a bridging alpha helix. The SARS coronavirus has actually been the source of a surprising number of new protein folds: of the 16 structures that are currently available, 8 show a new fold. This may be a reflection of the rapid evolution of viruses, which allows more room for natural experimentation with new protein folds.

This picture was created with the Python Molecule Viewer. The JSmol tab below displays an interactive JSmol. For a high resolution tif image, click here.

Aspartate Dehydrogenase (PDB entry 1j5p)

The presumed active site of aspartate dehydrogenase is found in a deep pocket which holds the substrate aspartate and the cofactor NAD. This structure includes NAD bound in the active site (colored with atomic colors), but it doesn't include the substrate. A nearby histidine (colored magenta) is thought to be an important for catalyzing the reaction.

References

  1. M. S. Almeida, M .A. Johnson, T. Herrmann, M. Geralt and K. Wuthrich (2007) Novel beta-barrel fold in the nuclear magnetic resonance structure of the replicase nonstructural protein 1 from severe acute respiratory syndrome coronavirus. Journal of Virology 81, 3151-3161.

  2. M. Bartlam, Y. Xu and Z. Rao (2007) Structural proteomics of the SARS coronavirus: a model response to emerging infectious disease. Journal of Structural and Functional Genomics 8, 85-97.

Structural Biology Knowledgebase ISSN: 1758-1338
Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health