Exploring the dark side of tertiary and quaternary structure dynamics in FBPaseII.

Tuberculosis (TB) is a major global cause of mortality, primarily stemming from latent tuberculosis infection (LTBI). Failure to fully treat LTBI can result in drug-resistant forms of TB. Therefore, it is essential to develop novel drugs with unique mechanisms of action to combat TB effectively.

New structures of Class II Fructose-1,6-Bisphosphatase from Francisella tularensis provide a framework for a novel catalytic mechanism for the entire class.

Class II Fructose-1,6-bisphosphatases (FBPaseII) (EC: 3.1.3.

Notes of a protein crystallographer: the advantages of combining new integrated methods of structure solution with traditional data visuals.

The suggestion is made that combining analysis using the most advanced crystallographic software with the integrated visual tools of the field will result in more knowledgeable and better trained future generations of structural biologists. The use of integrated visuals could also expedite the structure solution of some recalcitrant and complex macromolecular crystal structures that resist automatic workflows.

Notes of a protein crystallographer: the legacy of J.-B. J. Fourier - crystallography, time and beyond.

The importance of the Fourier transform as a fundamental tool for crystallography is well known in the field. However, the complete legacy of Jean-Baptiste Joseph Fourier (1768-1830) as a pioneer Egyptologist and premier mathematician and physicist of his time, and the implications of his work in other scientific fields, is less well known. Significantly, his theoretical and experimental work on phenomena related to the transmission of heat founded the mathematical study of irreversible phenomena and introduced the flow of time in physico-chemical processes and geology, with its implications for biological evolution.

Ligand efficiency indices for effective drug discovery: a unifying vector formulation.

Introduction: The area of ligand efficiency indices (LEIs) in drug discovery has developed significantly since the initial publications nearly 20 years ago. A large number of different LEIs have been defined and applied with certain degrees of success and acceptance in the community. An overall view emphasizing more the common elements than the differences is needed.

Structural and biochemical characterization of the class II fructose-1,6-bisphosphatase from Francisella tularensis.

The crystal structure of the class II fructose-1,6-bisphosphatase (FBPaseII) from the important pathogen Francisella tularensis is presented at 2.4 Å resolution. Its structural and functional relationships to the closely related phosphatases from Mycobacterium tuberculosis (MtFBPaseII) and Escherichia coli (EcFBPaseII) and to the dual phosphatase from Synechocystis strain 6803 are discussed.

Structure of the N-terminal domain of ClpC1 in complex with the antituberculosis natural product ecumicin reveals unique binding interactions.

The biological processes related to protein homeostasis in Mycobacterium tuberculosis, the etiologic agent of tuberculosis, have recently been established as critical pathways for therapeutic intervention. Proteins of particular interest are ClpC1 and the ClpC1-ClpP1-ClpP2 proteasome complex. The structure of the potent antituberculosis macrocyclic depsipeptide ecumicin complexed with the N-terminal domain of ClpC1 (ClpC1-NTD) is presented here.

High-Resolution Structure of ClpC1-Rufomycin and Ligand Binding Studies Provide a Framework to Design and Optimize Anti-Tuberculosis Leads.

Addressing the urgent need to develop novel drugs against drug-resistant Mycobacterium tuberculosis ( M. tb) strains, ecumicin (ECU) and rufomycin I (RUFI) are being explored as promising new leads targeting cellular proteostasis via the caseinolytic protein ClpC1. Details of the binding topology and chemical mode of (inter)action of these cyclopeptides help drive further development of novel potency-optimized entities as tuberculosis drugs.

Structures of the Mycobacterium tuberculosis GlpX protein (class II fructose-1,6-bisphosphatase): implications for the active oligomeric state, catalytic mechanism and citrate inhibition.

The crystal structures of native class II fructose-1,6-bisphosphatase (FBPaseII) from Mycobacterium tuberculosis at 2.6 Å resolution and two active-site protein variants are presented. The variants were complexed with the reaction product fructose 6-phosphate (F6P).

Mutagenesis of threonine to serine in the active site of fructose-1,6-bisphosphatase (Class II) retains partial enzyme activity.

The gene encodes for the Class II fructose-1,6-bisphosphatase enzyme in (), an essential enzyme for pathogenesis. We have performed site directed mutagenesis to introduce two mutations at residue Thr84, T84A and T84S, to explore the binding affinity of the substrate and the catalytic mechanism. The T84A mutant fully abolishes enzyme activity while retaining substrate binding affinity.

Structures of SAICAR synthetase (PurC) from Streptococcus pneumoniae with ADP, Mg2+, AIR and Asp.

Streptococcus pneumoniae is a multidrug-resistant pathogen that is a target of considerable interest for antibacterial drug development. One strategy for drug discovery is to inhibit an essential metabolic enzyme. The seventh step of the de novo purine-biosynthesis pathway converts carboxyaminoimidazoleribonucleotide (CAIR) and L-aspartic acid (Asp) to 4-(N-succino)-5-aminoimidazole-4-carboxamide ribonucleotide (SAICAR) in the presence of adenosine 5'-triphosphate (ATP) using the enzyme PurC.

Ask the experts: past, present and future of the rule of five.

Coined in 1997, by Christopher Lipinki et al., the rule of five (Ro5) comprises a set of parameters that determine drug-likeness for oral delivery. The parameters are as follows: no more than five hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms); no more than ten hydrogen bond acceptors (nitrogen or oxygen atoms); a molecular mass less than 500 Da; and an octanol-water partition coefficient log P no greater than 5.

Benzoxazole benzenesulfonamides as allosteric inhibitors of fructose-1,6-bisphosphatase.

A series of novel benzoxazole benzenesulfonamides was synthesized as inhibitors of fructose-1,6-bisphosphatase (FBPase-1). Extensive SAR studies led to a potent inhibitor, 53, with an IC(50) of 0.57microM.

Benzoxazole benzenesulfonamides are novel allosteric inhibitors of fructose-1,6-bisphosphatase with a distinct binding mode.

We have identified benzoxazole benzenesulfonamide 1 as a novel allosteric inhibitor of fructose-1,6-bisphosphatase (FBPase-1). X-ray crystallographic and biological studies of 1 indicate a distinct binding mode that recapitulates features of several previously reported FBPase-1 inhibitor classes.