scholarly journals A processive rotary mechanism couples substrate unfolding and proteolysis in the ClpXP degradation machinery

2019 ◽  
Author(s):  
Zev A. Ripstein ◽  
Siavash Vahidi ◽  
Walid A. Houry ◽  
John L. Rubinstein ◽  
Lewis E. Kay
Keyword(s):  
Infectious Diseases ◽  
Drug Development ◽  
Molecular Machines ◽  
Common Mechanism ◽  
Important Target ◽  
Rotary Mechanism ◽  
Growing Body ◽  
Client Proteins ◽  
Hydrolysis Of ◽  
Proteolytic Chamber

AbstractThe ClpXP degradation machine consists of a hexameric AAA+ unfoldase (ClpX) and a pair of heptameric serine protease rings (ClpP) that unfold, translocate, and subsequently degrade client proteins. ClpXP is an important target for drug development against infectious diseases. Although structures are available for isolated ClpX and ClpP rings, it remains unknown how symmetry mismatched ClpX and ClpP work in tandem for processive substrate translocation into the ClpP proteolytic chamber. Here we present cryo-EM structures of the substrate-bound ClpXP complex from Neisseria meningitidis at 2.3 to 3.3 Å resolution. The structures allow development of a model in which the cyclical hydrolysis of ATP is coupled to concerted motions of ClpX loops that lead to directional substrate translocation and ClpX rotation relative to ClpP. Our data add to the growing body of evidence that AAA+ molecular machines generate translocating forces by a common mechanism.

scholarly journals A processive rotary mechanism couples substrate unfolding and proteolysis in the ClpXP degradation machinery

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Zev A Ripstein ◽  
Siavash Vahidi ◽  
Walid A Houry ◽  
John L Rubinstein ◽  
Lewis E Kay
Keyword(s):  
Infectious Diseases ◽  
Drug Development ◽  
Molecular Machines ◽  
Common Mechanism ◽  
Important Target ◽  
Rotary Mechanism ◽  
Growing Body ◽  
Client Proteins ◽  
Hydrolysis Of ◽  
Proteolytic Chamber

The ClpXP degradation machine consists of a hexameric AAA+ unfoldase (ClpX) and a pair of heptameric serine protease rings (ClpP) that unfold, translocate, and subsequently degrade client proteins. ClpXP is an important target for drug development against infectious diseases. Although structures are available for isolated ClpX and ClpP rings, it remains unknown how symmetry mismatched ClpX and ClpP work in tandem for processive substrate translocation into the ClpP proteolytic chamber. Here, we present cryo-EM structures of the substrate-bound ClpXP complex from Neisseria meningitidis at 2.3 to 3.3 Å resolution. The structures allow development of a model in which the sequential hydrolysis of ATP is coupled to motions of ClpX loops that lead to directional substrate translocation and ClpX rotation relative to ClpP. Our data add to the growing body of evidence that AAA+ molecular machines generate translocating forces by a common mechanism.

scholarly journals Remodeler Catalyzed Nucleosome Repositioning: Influence of Structure and Stability

2020 ◽  
Vol 22 (1) ◽  
pp. 76
Author(s):  
Aaron Morgan ◽  
Sarah LeGresley ◽  
Christopher Fischer
Keyword(s):  
Free Energy ◽  
Dna Replication ◽  
Recent Work ◽  
Chromatin Remodeling ◽  
Chromatin Structure ◽  
Genetic Information ◽  
Molecular Machines ◽  
Mechanical Work ◽  
Eukaryotic Genome ◽  
Hydrolysis Of

The packaging of the eukaryotic genome into chromatin regulates the storage of genetic information, including the access of the cell’s DNA metabolism machinery. Indeed, since the processes of DNA replication, translation, and repair require access to the underlying DNA, several mechanisms, both active and passive, have evolved by which chromatin structure can be regulated and modified. One mechanism relies upon the function of chromatin remodeling enzymes which couple the free energy obtained from the binding and hydrolysis of ATP to the mechanical work of repositioning and rearranging nucleosomes. Here, we review recent work on the nucleosome mobilization activity of this essential family of molecular machines.

scholarly journals NB2001, a Novel Antibacterial Agent with Broad-Spectrum Activity and Enhanced Potency against β-Lactamase-Producing Strains

2002 ◽  
Vol 46 (5) ◽  
pp. 1262-1268 ◽  
Author(s):  
Qing Li ◽  
Jean Y. Lee ◽  
Rosario Castillo ◽  
Mark S. Hixon ◽  
Catherine Pujol ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Antibacterial Agent ◽  
Bacterial Resistance ◽  
Enterobacter Aerogenes ◽  
Order Rate Constant ◽  
Common Mechanism ◽  
E Coli ◽  
Lactam Ring ◽  
Spectrum Activity ◽  
Hydrolysis Of

ABSTRACT Enzyme-catalyzed therapeutic activation (ECTA) is a novel prodrug strategy to overcome drug resistance resulting from enzyme overexpression. β-Lactamase overexpression is a common mechanism of bacterial resistance to β-lactam antibiotics. We present here the results for one of the β-lactamase ECTA compounds, NB2001, which consists of the antibacterial agent triclosan in a prodrug form with a cephalosporin scaffold. Unlike conventional β-lactam antibiotics, where hydrolysis of the β-lactam ring inactivates the antibiotic, hydrolysis of NB2001 by β-lactamase releases triclosan. Evidence supporting the proposed mechanism is as follows. (i) NB2001 is a substrate for TEM-1 β-lactamase, forming triclosan with a second-order rate constant (k cat/Km ) of greater than 77,000 M−1 s−1. (ii) Triclosan is detected in NB2001-treated, β-lactamase-producing Escherichia coli but not in E. coli that does not express β-lactamase. (iii) NB2001 activity against β-lactamase-producing E. coli is decreased in the presence of the β-lactamase inhibitor clavulanic acid. NB2001 was similar to or more potent than reference antibiotics against clinical isolates of Staphylococcus aureus (including MRSA), Staphylococcus epidermidis, Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis, Moraxella catarrhalis and Haemophilus influenzae. NB2001 is also active against Klebsiella pneumoniae, Enterobacter aerogenes, and Enterobacter cloacae. The results indicate that NB2001 is a potent, broad-spectrum antibacterial agent and demonstrate the potential of ECTA in overcoming β-lactamase-mediated resistance.

Genomics, systems biology and drug development for infectious diseases

2007 ◽  
Vol 3 (12) ◽  
pp. 841 ◽  
Author(s):  
Tomoyo Sakata ◽  
Elizabeth A. Winzeler
Keyword(s):  
Systems Biology ◽  
Infectious Diseases ◽  
Drug Development

scholarly journals Toward an Evidence-Based Nonclinical Road Map for Evaluating the Efficacy of New Tuberculosis (TB) Drug Regimens: Proceedings of a Critical Path to TB Drug Regimens-National Institute of Allergy and Infectious DiseasesIn VivoPharmacology Workshop for TB Drug Development

2016 ◽  
Vol 60 (3) ◽  
pp. 1177-1182 ◽  
Author(s):  
Eric Nuermberger ◽  
Christine Sizemore ◽  
Klaus Romero ◽  
Debra Hanna
Keyword(s):  
Infectious Diseases ◽  
Drug Development ◽  
Drug Combination ◽  
Critical Path ◽  
Evidence Based ◽  
Road Map ◽  
Drug Regimens ◽  
Combination Regimens ◽  
Selection Of

Novel tuberculosis (TB) drug regimens are urgently needed, and their development will be enabled by improved preclinical approaches that more effectively inform and ensure safe selection of clinical candidates and drug combination/regimens. An evidence-based approach for the assessment of nonclinical models supporting TB drug development has been proposed by a joint partnership between the National Institute of Allergy and Infectious Diseases (NIAID) and the Critical Path to TB Drug Regimens (CPTR) Consortium.

Individual differences in pathogen disgust predict responses to trypophobic images

2019 ◽  
Author(s):  
Laura McAuley ◽  
Victor Kenji Medeiros Shiramizu ◽  
Kieran J. O'Shea ◽  
Judith stevenson ◽  
Benedict C Jones ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Individual Differences ◽  
Infectious Diseases ◽  
Recent Work ◽  
Growing Body ◽  
Sexual Disgust ◽  
Small Holes

Pathogen disgust is thought to function primarily to reduce exposure to infectious diseases. Recent work has found that viewing trypophobic images (i.e., images showing clusters of small holes or bumps) elicits stronger negative responses in people who report greater pathogen disgust. This association has been reported for responses to trypophobic images that pose no obvious threat of infectious disease (i.e., infectious-disease-unrelated images) and is independent of the possible effects of disgust in other domains (e.g., moral or sexual disgust). In a sample of 494 participants, we replicated the finding that pathogen disgust, but not moral or sexual disgust, predicted individual differences in the extent to which infectious-disease-unrelated images (a lotus pod and a honeycomb) elicited negative responses. These results contribute to a growing body of work that may implicate pathogen disgust in a range of attitudes to individuals, groups, and objects, even when they pose no obvious threat of infectious disease.

scholarly journals Extensive hybridization reveals multiple coloration genes underlying a complex plumage phenotype

2021 ◽  
Vol 288 (1943) ◽  
pp. 20201805
Author(s):  
Stepfanie M. Aguillon ◽  
Jennifer Walsh ◽  
Irby J. Lovette
Keyword(s):  
Genetic Basis ◽  
Carotenoid Pigments ◽  
Important Target ◽  
Carotenoid Coloration ◽  
Genome Wide ◽  
Growing Body ◽  
Genomic Regions ◽  
Carotenoid Pigmentation ◽  
Specific Control ◽  
Natural And Sexual Selection

Coloration is an important target of both natural and sexual selection. Discovering the genetic basis of colour differences can help us to understand how this visually striking phenotype evolves. Hybridizing taxa with both clear colour differences and shallow genomic divergences are unusually tractable for associating coloration phenotypes with their causal genotypes. Here, we leverage the extensive admixture between two common North American woodpeckers—yellow-shafted and red-shafted flickers—to identify the genomic bases of six distinct plumage patches involving both melanin and carotenoid pigments. Comparisons between flickers across approximately 7.25 million genome-wide SNPs show that these two forms differ at only a small proportion of the genome (mean F ST = 0.008). Within the few highly differentiated genomic regions, we identify 368 SNPs significantly associated with four of the six plumage patches. These SNPs are linked to multiple genes known to be involved in melanin and carotenoid pigmentation. For example, a gene ( CYP2J19 ) known to cause yellow to red colour transitions in other birds is strongly associated with the yellow versus red differences in the wing and tail feathers of these flickers. Additionally, our analyses suggest novel links between known melanin genes and carotenoid coloration. Our finding of patch-specific control of plumage coloration adds to the growing body of literature suggesting colour diversity in animals could be created through selection acting on novel combinations of coloration genes.

scholarly journals 14–3-3 protein regulation of excitation–contraction coupling

2021 ◽  
Author(s):  
Walter C. Thompson ◽  
Paul H. Goldspink
Keyword(s):  
Protein Interactions ◽  
Protein Function ◽  
Force Generation ◽  
Client Protein ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Cellular Processes ◽  
Disease States ◽  
Growing Body ◽  
Client Proteins

Abstract 14–3-3 proteins (14–3-3 s) are a family of highly conserved proteins that regulate many cellular processes in eukaryotes by interacting with a diverse array of client proteins. The 14–3-3 proteins have been implicated in several disease states and previous reviews have condensed the literature with respect to their structure, function, and the regulation of different cellular processes. This review focuses on the growing body of literature exploring the important role 14–3-3 proteins appear to play in regulating the biochemical and biophysical events associated with excitation–contraction coupling (ECC) in muscle. It presents both a timely and unique analysis that seeks to unite studies emphasizing the identification and diversity of 14–3-3 protein function and client protein interactions, as modulators of muscle contraction. It also highlights ideas within these two well-established but intersecting fields that support further investigation with respect to the mechanistic actions of 14–3-3 proteins in the modulation of force generation in muscle.

scholarly journals Multisystem Analysis ofMycobacterium tuberculosisReveals Kinase-Dependent Remodeling of the Pathogen-Environment Interface

mBio ◽  
2018 ◽  
Vol 9 (2) ◽  
Author(s):  
Xavier Carette ◽  
John Platig ◽  
David C. Young ◽  
Michaela Helmel ◽  
Albert T. Young ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Infectious Diseases ◽  
Drug Development ◽  
Protein Kinases ◽  
Lipid Content ◽  
Cell Envelope ◽  
Integrated Analysis ◽  
Protein Abundance ◽  
Valuable Resource ◽  
Mycobacterial Cell

ABSTRACTTuberculosis is the leading killer among infectious diseases worldwide. Increasing multidrug resistance has prompted new approaches for tuberculosis drug development, including targeted inhibition of virulence determinants and of signaling cascades that control many downstream pathways. We used a multisystem approach to determine the effects of a potent small-molecule inhibitor of the essentialMycobacterium tuberculosisSer/Thr protein kinases PknA and PknB. We observed differential levels of phosphorylation of many proteins and extensive changes in levels of gene expression, protein abundance, cell wall lipids, and intracellular metabolites. The patterns of these changes indicate regulation by PknA and PknB of several pathways required for cell growth, including ATP synthesis, DNA synthesis, and translation. These data also highlight effects on pathways for remodeling of the mycobacterial cell envelope via control of peptidoglycan turnover, lipid content, a SigE-mediated envelope stress response, transmembrane transport systems, and protein secretion systems. Integrated analysis of phosphoproteins, transcripts, proteins, and lipids identified an unexpected pathway whereby threonine phosphorylation of the essential response regulator MtrA decreases its DNA binding activity. Inhibition of this phosphorylation is linked to decreased expression of genes for peptidoglycan turnover, and of genes for mycolyl transferases, with concomitant changes in mycolates and glycolipids in the cell envelope. These findings reveal novel roles for PknA and PknB in regulating multiple essential cell functions and confirm that these kinases are potentially valuable targets for new antituberculosis drugs. In addition, the data from these linked multisystems provide a valuable resource for future targeted investigations into the pathways regulated by these kinases in theM. tuberculosiscell.IMPORTANCETuberculosis is the leading killer among infectious diseases worldwide. Increasing drug resistance threatens efforts to control this epidemic; thus, new antitubercular drugs are urgently needed. We performed an integrated, multisystem analysis ofMycobacterium tuberculosisresponses to inhibition of its two essential serine/threonine protein kinases. These kinases allow the bacterium to adapt to its environment by phosphorylating cellular proteins in response to extracellular signals. We identified differentially phosphorylated proteins, downstream changes in levels of specific mRNA and protein abundance, and alterations in the metabolite and lipid content of the cell. These results include changes previously linked to growth arrest and also reveal new roles for these kinases in regulating essential processes, including growth, stress responses, transport of proteins and other molecules, and the structure of the mycobacterial cell envelope. Our multisystem data identify PknA and PknB as promising targets for drug development and provide a valuable resource for future investigation of their functions.

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