2-Aminoquinazolin-4(3H)-ones were identified as a novel class of malaria digestive vacuole plasmepsin inhibitors by using NMR-based fragment screening against Plm II. Initial hit optimization led to submicromolar inhibitor, which was cocrystallized with II produce an X-ray structure the complex. The showed that 2-aminoquinazolin-4(3H)-ones bind open flap conformation enzyme and provided clues target pocket. Further improvement in potency achieved via introduction hydrophobic substituents...

Inhibitors of human mast cell tryptase (EC 3.4.21.59) have therapeutic potential for treating allergic or inflammatory disorders. We investigated transition-state mimetics possessing a heterocycle-activated ketone group and identified in particular benzothiazole (2S)-6 (RWJ-56423) as potent, reversible, low-molecular-weight inhibitor with K(i) value 10 nM. A single-crystal X-ray analysis the sulfate salt confirmed stereochemistry. Analogues 12 15-17 are also potent inhibitors. Although...

Apolipoprotein B-containing lipoproteins (B-lps) are essential for the transport of hydrophobic dietary and endogenous lipids through circulation in vertebrates. Zebrafish embryos produce large numbers B-lps yolk syncytial layer (YSL) to move from growing tissues. Disruptions B-lp production perturb morphology, readily allowing visual identification mutants with altered metabolism. Here we report discovery a missense mutation microsomal triglyceride transfer protein (Mtp), that is...

Abstract Cell surface aminopeptidase N (APN) is a membrane-bound ectoenzyme that hydrolyzes proteins and peptides regulates numerous cell functions. APN participates in tumor expansion motility, target for cancer therapies. Small drugs bind to the active site inhibit catalysis suppress growth. also major entry receptor coronavirus, which binds region distant from site. Three crystal structures we determined of human pig ectodomains defined dynamic conformation protein. These offered...

The serine protease cathepsin G (EC 3.4.21.20; Cat G), which is stored in the azurophilic granules of neutrophils (polymorphonuclear leukocytes) and released on degranulation, has been implicated various pathological conditions associated with inflammation. By employing high-throughput screening, we identified beta-ketophosphonic acid 1 as a moderate inhibitor (IC(50) = 4.1 microM). We were fortunate to obtain cocrystal solve its structure by X-ray crystallography (3.5 A). Structural details...

Abstract Global health challenges such as the coronavirus pandemic warrant urgent need for a system that allows efficient production of diagnostic and therapeutic interventions. Antibody treatments against SARS-CoV-2 were developed with an unprecedented pace this enormous progress was achieved mainly through recombinant protein technologies combined expeditious screening approaches. A heterologous soluble antibody candidates rapidly evolving variants deadly pathogens is important step in...

Hyperlipidemia predisposes individuals to cardiometabolic diseases, the most common cause of global mortality. Microsomal triglyceride transfer protein (MTP) transfers multiple lipids and is essential for assembly apolipoprotein B-containing lipoproteins. MTP inhibition lowers plasma but causes lipid retention in liver intestine. Previous studies suggested two domains that specific (TG) not phospholipid (PL) can lower without significant tissue accumulation. However, how different involved...

The fructose-based sugar sulphamate RWJ-37497, a potent analogue of the widely used anti-epileptic drug topiramate, possesses anti-convulsant and carbonic anhydrase-inhibitory activities. We have studied binding interactions RWJ-37497 in active site human anhydrase II by X-ray crystallography. atomic positions enzyme inhibitor complex were refined at resolution 2.1 Å (1 = 0.1 nm) to final crystallographic R Rfree values 0.18 0.23, respectively. co-ordinates active-site zinc ion through its...

The fructose-based sugar sulphamate RWJ-37497, a potent analogue of the widely used anti-epileptic drug topiramate, possesses anti-convulsant and carbonic anhydrase-inhibitory activities. We have studied binding interactions RWJ-37497 in active site human anhydrase II by X-ray crystallography. atomic positions enzyme inhibitor complex were refined at resolution 2.1 Å (1 = 0.1 nm) to final crystallographic R Rfree values 0.18 0.23, respectively. co-ordinates active-site zinc ion through its...

Plasmepsin II (PMII) is one of the ten plasmepsins (PMs) identified in genome Plasmodium falciparum, causative agent most severe and deadliest form malaria. Owing to emergence P. falciparum strains that are resistant current antimalarial agents such as chloroquine sulfadoxine/pyrimethamine, there a constant pressure find new lasting chemotherapeutic drug therapies. Previously, crystal structure PMII complex with NU655, potent hydroxyethylamine-based inhibitor, design compounds based on it...

Rab proteins are small Ras-like GTPases which play important roles in regulating intracellular vesicle trafficking. The nucleotide-binding domain of Rab6 from the malaria parasite Plasmodium falciparum was crystallized with GDP bound to active site. MAD phasing technique used determine crystal structure 2.3 Å resolution. Comparisons GDP-bound PfRab6 recently determined structures Rab3A complex either a GTP analog or and Rabphillin present structural evidence supporting traditional model for...

Intercellular cell adhesion molecule-5 (ICAM-5) is a member of the ICAM subfamily that exclusively expressed in telencephalon region brain. The crystal structure four most N-terminal glycosylated domains (D1–D4) ICAM-5 was determined three different space groups and D1–D5 fragment modelled. structures showed curved molecule with two pronounced interdomain bends between D2 D3 D4, as well some flexibility. In contrast to ICAM-1, has patches positive negative electrostatic charge at D1–D2...

Plasmepsin IV from Plasmodium falciparum (PM IV) is a promising target for the development of novel antimalarial drugs. Here, crystal structure truncated zymogen PM (pPM IV), consisting mature enzyme plus prosegment 47 residues, has been determined at 1.5 Å resolution. pPM presents fold previously described studied proplasmepsins, displaying closer similarities to proplasmepin P. vivax (p Pv PM) than other two proplasmepsins . The study and comparison with proplasmepsin structures provide...

The obligate intracellular protozoan parasite Toxoplasma gondii depends on the purine-salvage pathway for its purine supply. Unlike mammalian hosts, T. salvages precursors predominantly via adenosine kinase, enzyme that phosphorylates to monophosphate (AMP). cDNA encoding kinase was subcloned and expressed in Escherichia coli. recombinant protein active an vitro assay over a broad pH range. It required divalent cation activity. inactivated by addition of 1 microM mercuric chloride....

Hyperlipidemia predispose individuals to cardio-metabolic diseases, the most common cause of global mortality. Microsomal triglyceride transfer protein (MTP) transfers multiple lipids and is essential for assembly apoB-containing lipoproteins. MTP inhibition lowers plasma but causes lipid retention in liver intestine. Previous studies suggested two domains that specific triglycerides (TG) not phospholipids (PL) can lower without significant tissue accumulation. However, how different...

The three-dimensional structure of bovine pancreatic trypsin complexed with the inhibitor RWJ-51084 has been determined at 1.8 A resolution. These crystals belong to trigonal space group P3(1)21, unit-cell parameters a = b 53.43, c 107.76 A. refined R and R(free) values are 0.175 0.237, respectively. carbonyl bonded benzothiazole is covalently linked hydroxyl O atom Ser195, forming tetrahedral intermediate hemiketal structure. other forms hydrogen bond Gln192 side-chain amide group. oriented...

The three-dimensional structure of the ternary complex consisting human α-thrombin, hirugen and active-site inhibitor RWJ-51438 has been determined at 1.7 Å resolution. crystals belong to orthorhombic space group P21212, with unit-cell parameters a = 62.98, b 117.52, c 47.99 Å. refined R Rfree values are 0.196 0.232, respectively. ketone carbonyl is covalently linked hydroxyl O atom Ser195, forming tetrahedral intermediate hemiketal structure; benzothiazole ring N forms hydrogen bond His57....

The major cat allergen Fel d 1 is one of the most common and potent causes animal related allergy. Medical treatment allergy has relied on immunotherapy carried out with dander extract. This approach been problematic, mainly due to inconsistent levels in produced extracts. Recombinant DNA technology proposed as an alternative method produce more consistent pharmaceuticals for diagnostics Current approaches recombinant (recFel 1) cytoplasm Escherichia coli have however resulted protein...

The title compound crystallizes in the zwitterionic form. crystal forms a supramolecular structure with peptide molecules organized head‐to‐tail columns b direction. arginine side‐chains and acetate ions interact neighbor peptides c Infinite hydrophobic are present direction; they involve valine side‐chains, methyl groups methylene of side‐chains. This three‐dimensional organization is similar to that found Lys‐Val hydrochloride. © Munksgaard 1997.