Low-Barrier Hydrogen Bonding in Molecular Complexes Analogous to Histidine and Aspartate in the Catalytic Triad of Serine Proteases

Biochemistry ◽  
1995 ◽  
Vol 34 (21) ◽  
pp. 6919-6924 ◽  
Author(s):  
John B. Tobin ◽  
Sean A. Whitt ◽  
Constance S. Cassidy ◽  
Perry A. Frey
Keyword(s):  
Hydrogen Bonding ◽  
Serine Proteases ◽  
Molecular Complexes ◽  
Catalytic Triad

Strong N−H⋅⋅⋅O Hydrogen Bonding in a Model Compound of the Catalytic Triad in Serine Proteases

1999 ◽  
Vol 38 (9) ◽  
pp. 1239-1242 ◽  
Author(s):  
Jacob Overgaard ◽  
Birgit Schiøtt ◽  
Finn K. Larsen ◽  
Arthur J. Schultz ◽  
John C. MacDonald ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Serine Proteases ◽  
Model Compound ◽  
Catalytic Triad

The Herpesvirus Proteases as Targets for Antiviral Chemotherapy

2000 ◽  
Vol 11 (1) ◽  
pp. 1-22 ◽  
Author(s):  
Lloyd Waxman ◽  
Paul L Darke
Keyword(s):  
Serine Protease ◽  
Active Site ◽  
Serine Proteases ◽  
Catalytic Triad ◽  
Active Site Residues ◽  
Virus Family ◽  
Single Domain Protein ◽  
Inhibitor Discovery ◽  
Antiviral Chemotherapy ◽  
Simplex Virus

Viruses of the family Herpesviridae are responsible for a diverse set of human diseases. The available treatments are largely ineffective, with the exception of a few drugs for treatment of herpes simplex virus (HSV) infections. For several members of this DNA virus family, advances have been made recently in the biochemistry and structural biology of the essential viral protease, revealing common features that may be possible to exploit in the development of a new class of anti-herpesvirus agents. The herpesvirus proteases have been identified as belonging to a unique class of serine protease, with a Ser-His-His catalytic triad. A new, single domain protein fold has been determined by X-ray crystallography for the proteases of at least three different herpesviruses. Also unique for serine proteases, dimerization has been shown to be required for activity of the cytomegalovirus and HSV proteases. The dimerization requirement seriously impacts methods needed for productive, functional analysis and inhibitor discovery. The conserved functional and catalytic properties of the herpesvirus proteases lead to common considerations for this group of proteases in the early phases of inhibitor discovery. In general, classical serine protease inhibitors that react with active site residues do not readily inactivate the herpesvirus proteases. There has been progress however, with activated carbonyls that exploit the selective nucleophilicity of the active site serine. In addition, screening of chemical libraries has yielded novel structures as starting points for drug development. Recent crystal structures of the herpesvirus proteases now allow more direct interpretation of ligand structure—activity relationships. This review first describes basic functional aspects of herpesvirus protease biology and enzymology. Then we discuss inhibitors identified to date and the prospects for their future development.

scholarly journals Identification and expression of Pen c 2, a novel allergen from Penicillium citrinum

1999 ◽  
Vol 341 (1) ◽  
pp. 51-59 ◽  
Author(s):  
Lu-Ping CHOW ◽  
Ning-Yuan SU ◽  
Chia-Jung YU ◽  
Bor-Luen CHIANG ◽  
Horng-Der SHEN
Keyword(s):  
Amino Acid ◽  
Serine Proteases ◽  
Catalytic Triad ◽  
Penicillium Citrinum ◽  
E Coli ◽  
Acid Protein ◽  
Amino Acid Signal Peptide ◽  
Cloned Cdna ◽  
Allergic Disorders ◽  
Amino Acid Protein

The mould genus, Penicillium, is known to be a significant source of environmental aero-allergens. One important allergen from Penicillium citrinum, Pen c 2, has been identified by means of two-dimensional immunoblotting using IgE-containing patients' sera. This novel allergen was cloned, sequenced and expressed in Escherichia coli. The cloned cDNA encodes a large 457-amino acid protein precursor containing a 16-amino acid signal peptide, a 120-amino acid propeptide and the 321-amino acid mature protein. Comparison of the Pen c 2 sequence with known protein sequences revealed shared high sequence similarities with two vacuolar serine proteases from Aspergillus niger and Saccharomyces cerevisiae. Asp-46, His-78 and Ser-244 were found to constitute the catalytic triad of the 39-kDa Pen c 2. The DNA coding for Pen c 2 was cloned into vector PQE-30 and expressed in E. coli as a His-tag fusion protein that bound serum IgE from Penicillium-allergic patients on immunoblots. Recombinant Pen c 2 could therefore be used effectively for diagnosis and also potentially for the treatment of mould-derived allergic disorders.

scholarly journals Three-Dimensional Molecular Modeling of a Diverse Range of SC Clan Serine Proteases

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Aparna Laskar ◽  
Aniruddha Chatterjee ◽  
Somnath Chatterjee ◽  
Euan J. Rodger
Keyword(s):  
Molecular Modeling ◽  
Structure Prediction ◽  
Serine Proteases ◽  
Three Dimensional ◽  
Catalytic Triad ◽  
Evolutionary Divergence ◽  
Catalytic Core ◽  
Diverse Range ◽  
Wide Range ◽  
Surface Electrostatic Potential

Serine proteases are involved in a variety of biological processes and are classified into clans sharing structural homology. Although various three-dimensional structures of SC clan proteases have been experimentally determined, they are mostly bacterial and animal proteases, with some from archaea, plants, and fungi, and as yet no structures have been determined for protozoa. To bridge this gap, we have used molecular modeling techniques to investigate the structural properties of different SC clan serine proteases from a diverse range of taxa. Either SWISS-MODEL was used for homology-based structure prediction or the LOOPP server was used for threading-based structure prediction. The predicted models were refined using Insight II and SCRWL and validated against experimental structures. Investigation of secondary structures and electrostatic surface potential was performed using MOLMOL. The structural geometry of the catalytic core shows clear deviations between taxa, but the relative positions of the catalytic triad residues were conserved. Evolutionary divergence was also exhibited by large variation in secondary structure features outside the core, differences in overall amino acid distribution, and unique surface electrostatic potential patterns between species. Encompassing a wide range of taxa, our structural analysis provides an evolutionary perspective on SC clan serine proteases.

Sign in / Sign up

Export Citation Format

Share Document