Inherent structural disorder and dimerisation of murine norovirus NS1-2 protein.

Human noroviruses are highly infectious viruses that cause the majority of acute, non-bacterial epidemic gastroenteritis cases worldwide. The first open reading frame of the norovirus RNA genome encodes for a polyprotein that is cleaved by the viral protease into six non-structural proteins. The first non-structural protein, NS1-2, lacks any significant sequence similarity to other viral or cellular proteins and limited information is available about the function and biophysical characteristics of this protein.

Structural features and kinetic characterization of alanine racemase from Staphylococcus aureus (Mu50).

Staphylococcus aureus is an opportunistic Gram-positive bacterium which causes a wide variety of diseases ranging from minor skin infections to potentially fatal conditions such as pneumonia, meningitis and septicaemia. The pathogen is a leading cause of nosocomial acquired infections, a problem that is exacerbated by the existence of methicillin- and glycopeptide antibiotic-resistant strains which can be challenging to treat. Alanine racemase (Alr) is a pyridoxal-5'-phosphate-dependent enzyme which catalyzes reversible racemization between enantiomers of alanine.

Elucidation of the protonation states of the catalytic residues in mtKasA: implications for inhibitor design.

KasA (β-ketoacyl ACP synthase I) is involved in the biosynthetic pathway of mycolic acids, an essential component of the cell wall in Mycobacterium tuberculosis. It was shown that KasA is essential for the survival of the pathogen and thus could serve as a new drug target for the treatment of tuberculosis. The active site of KasA was previously characterized by X-ray crystallography.

A slow, tight binding inhibitor of InhA, the enoyl-acyl carrier protein reductase from Mycobacterium tuberculosis.

InhA, the enoyl-ACP reductase in Mycobacterium tuberculosis is an attractive target for the development of novel drugs against tuberculosis, a disease that kills more than two million people each year. InhA is the target of the current first line drug isoniazid for the treatment of tuberculosis infections. Compounds that directly target InhA and do not require activation by the mycobacterial catalase-peroxidase KatG are promising candidates for treating infections caused by isoniazid-resistant strains.

Slow onset inhibition of bacterial beta-ketoacyl-acyl carrier protein synthases by thiolactomycin.

Thiolactomycin (TLM), a natural product thiolactone antibiotic produced by species of Nocardia and Streptomyces, is an inhibitor of the beta-ketoacyl-acyl carrier protein synthase (KAS) enzymes in the bacterial fatty acid synthase pathway. Using enzyme kinetics and direct binding studies, TLM has been shown to bind preferentially to the acyl-enzyme intermediates of the KASI and KASII enzymes from Mycobacterium tuberculosis and Escherichia coli. These studies, which utilized acyl-enzyme mimics in which the active site cysteine was replaced by a glutamine, also revealed that TLM is a slow onset inhibitor of the KASI enzymes KasA and ecFabB but not of the KASII enzymes KasB and ecFabF.

Crystal structures of Mycobacterium tuberculosis KasA show mode of action within cell wall biosynthesis and its inhibition by thiolactomycin.

Mycobacteria have a unique cell wall consisting of mycolic acids, very-long-chain lipids that provide protection and allow the bacteria to persist within human macrophages. Inhibition of cell wall biosynthesis is fatal for the organism and a starting point for the discovery and development of novel antibiotics. We determined the crystal structures of KasA, a key enzyme involved in the biosynthesis of long-chain fatty acids, in its apo-form and bound to the natural product inhibitor thiolactomycin.

How an agonist peptide mimics the antibiotic tetracycline to induce Tet-repressor.

A 16-residue peptide, called Tip, induces the tetracycline repressor TetR as efficiently as the antibiotic tetracycline when fused to the N or C terminus of another protein. This is unusual because the majority of in vitro selected peptides, such as Tip, inhibit protein function, and agonist peptides are only rarely identified. We elucidated the atomic mechanism of TetR induction by Tip from crystal structures of TetR in complex with Tip and of free TetR.