ABSTRACT
Ribosomes from Mycobacterium tuberculosis (Mtb) possess species-specific ribosomal RNA (rRNA) expansion segments and ribosomal proteins (rProtein). Here, we present the near-atomic structures of the Mtb 50S ribosomal subunit and the complete Mtb 70S ribosome, solved by cryo-electron microscopy. Upon joining of the large and small ribosomal subunits, a 100-nt long expansion segment of the Mtb 23S rRNA, named H54a or the 'handle', switches interactions from with rRNA helix H68 and rProtein uL2 to with rProtein bS6, forming a new intersubunit bridge 'B9'. In Mtb 70S, bridge B9 is mostly maintained, leading to correlated motions among the handle, the L1 stalk and the small subunit in the rotated and non-rotated states. Two new protein densities were discovered near the decoding center and the peptidyl transferase center, respectively. These results provide a structural basis for studying translation in Mtb as well as developing new tuberculosis drugs.
Subject(s)
Mycobacterium tuberculosis/chemistry , Ribosomes/chemistry , Cryoelectron Microscopy , Models, Molecular , Motion , Mycobacterium smegmatis/chemistry , Protein Synthesis Inhibitors , Ribosomal Proteins/chemistry , Ribosome Subunits, Large, Bacterial/chemistry , Species SpecificityABSTRACT
The dissociated glucocorticoid receptor (GR) agonist ZK 216348 is rendered GR-selective over other nuclear hormone receptors through replacing the methylbenzoxazine with a quinoline moiety. Compounds were shown to be efficacious in cell assays with respect to inflammation endpoints, along with reduced activity in a transactivation assay, hinting at an improved therapeutic window over corticosteroids.
Subject(s)
Anti-Inflammatory Agents/chemistry , Quinolines/chemistry , Receptors, Glucocorticoid/agonists , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Cell Line , Drug Evaluation, Preclinical , Genes, Reporter/genetics , Humans , Quinolines/chemical synthesis , Quinolines/pharmacology , Receptors, Glucocorticoid/metabolism , Transcriptional ActivationABSTRACT
In this Letter we report the synthesis and evaluation of a series of non-amidine inhibitors of Urokinase Plasminogen Activator (uPA). Starting from compound 1, a significant change provided compounds in which the amidine, binding in the S1 pocket, was replaced with a primary amine. Further modifications led to the identification of potent, selective, and orally bioavailable uPA inhibitors.
Subject(s)
Benzylamines/chemistry , Serine Proteinase Inhibitors/chemistry , Urokinase-Type Plasminogen Activator/antagonists & inhibitors , Administration, Oral , Amidines/chemistry , Animals , Binding Sites , Crystallography, X-Ray , Humans , Rats , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/chemical synthesis , Structure-Activity Relationship , Urokinase-Type Plasminogen Activator/metabolismABSTRACT
Compound libraries have an important role in the drug discovery process. Various computational methods are available as decision support tools for medicinal chemists involved in compound library synthesis programs. These methods can be used to assemble a flexible library design scheme consisting of a structure-based library design followed by property-biased library refinement and final selection according to structure-activity-relationship considerations.
