scholarly journals Molecular basis of selectivity and activity for the antimicrobial peptide Lynronne‐1 informs rational design of peptide with improved activity

ChemBioChem ◽  
2021 ◽  
Author(s):  
Eleanor S. Jayawant ◽  
Jack Hutchinson ◽  
Dorota Gasparíková ◽  
Christine Lockey ◽  
Lidόn Pruñonosa Lara ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Molecular Basis ◽  
Rational Design

scholarly journals Rational design of syn-safencin, a novel linear antimicrobial peptide derived from the circular bacteriocin safencin AS-48

2018 ◽  
Vol 71 (6) ◽  
pp. 592-600 ◽  
Author(s):  
Francisco R. Fields ◽  
Katelyn E. Carothers ◽  
Rashna D. Balsara ◽  
Victoria A. Ploplis ◽  
Francis J. Castellino ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Rational Design ◽  
Circular Bacteriocin

Molecular basis for pore blockade of human Na+ channel Nav1.2 by the μ-conotoxin KIIIA

Science ◽  
2019 ◽  
Vol 363 (6433) ◽  
pp. 1309-1313 ◽  
Author(s):  
Xiaojing Pan ◽  
Zhangqiang Li ◽  
Xiaoshuang Huang ◽  
Gaoxingyu Huang ◽  
Shuai Gao ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Rational Design ◽  
Na Channel ◽  
Auxiliary Subunit ◽  
Cryo Electron Microscopy ◽  
Initiation And Propagation ◽  
The Central Nervous System ◽  
Immunoglobulin Domain ◽  
Pore Domain ◽  
Pore Blocker

The voltage-gated sodium channel Nav1.2 is responsible for the initiation and propagation of action potentials in the central nervous system. We report the cryo–electron microscopy structure of human Nav1.2 bound to a peptidic pore blocker, the μ-conotoxin KIIIA, in the presence of an auxiliary subunit, β2, to an overall resolution of 3.0 angstroms. The immunoglobulin domain of β2 interacts with the shoulder of the pore domain through a disulfide bond. The 16-residue KIIIA interacts with the extracellular segments in repeats I to III, placing Lys7 at the entrance to the selectivity filter. Many interacting residues are specific to Nav1.2, revealing a molecular basis for KIIIA specificity. The structure establishes a framework for the rational design of subtype-specific blockers for Nav channels.

scholarly journals Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches

2020 ◽  
Vol 19 (11) ◽  
pp. 4291-4315
Author(s):  
Antonio Francés-Monerris ◽  
Cécilia Hognon ◽  
Tom Miclot ◽  
Cristina García-Iriepa ◽  
Isabel Iriepa ◽  
...  
Keyword(s):  
Modeling And Simulation ◽  
Molecular Basis ◽  
Rational Design ◽  
Antiviral Agents

scholarly journals Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol

2018 ◽  
Author(s):  
Kelly A. Manthei ◽  
Shyh-Ming Yang ◽  
Bolormaa Baljinnyam ◽  
Louise Chang ◽  
Alisa Glukhova ◽  
...  
Keyword(s):  
Small Molecules ◽  
Molecular Basis ◽  
Rational Design ◽  
Therapeutic Potential ◽  
Hdl Cholesterol ◽  
Cholesterol Transport ◽  
Active Conformation ◽  
Lecithin:Cholesterol Acyltransferase ◽  
Functional Studies ◽  
Lcat Deficiency

ABSTRACTLecithin:cholesterol acyltransferase (LCAT) and LCAT-activating small molecules are being investigated as treatments for coronary heart disease (CHD) and familial LCAT deficiency (FLD). Herein we report the crystal structure of LCAT bound to a potent activator and an acyl intermediate-like inhibitor, thereby revealing an active conformation of LCAT and that the activator is bound exclusively to its membrane-binding domain (MBD). Functional studies indicate that the compound does not modulate the affinity of LCAT for HDL, but instead stabilizes residues in the MBD and likely facilitates channeling of substrates into the active site. By demonstrating that these activators increase the activity of an FLD variant, we show that compounds targeting the MBD have therapeutic potential. In addition, our data better define the acyl binding site of LCAT and pave the way for rational design of LCAT agonists and improved biotherapeutics for augmenting or restoring reverse cholesterol transport in CHD and FLD patients.

EPOXIDE HYDROLASES: Mechanisms, Inhibitor Designs, and Biological Roles

2005 ◽  
Vol 45 (1) ◽  
pp. 311-333 ◽  
Author(s):  
Christophe Morisseau ◽  
Bruce D. Hammock
Keyword(s):  
Cancer Progression ◽  
Molecular Basis ◽  
Rational Design ◽  
Catalytic Mechanism ◽  
Substrate Selectivity ◽  
Epoxide Hydrolases ◽  
Solid Foundation ◽  
Novel Drug ◽  
Regulation Of Blood Pressure ◽  
Chemical Mediators

Organisms are exposed to epoxide-containing compounds from both exogenous and endogenous sources. In mammals, the hydration of these compounds by various epoxide hydrolases (EHs) can not only regulate their genotoxicity but also, for lipid-derived epoxides, their endogenous roles as chemical mediators. Recent findings suggest that the EHs as a family represent novel drug discovery targets for regulation of blood pressure, inflammation, cancer progression, and the onset of several other diseases. Knowledge of the EH mechanism provides a solid foundation for the rational design of inhibitors, and this review summarizes the current understanding of the catalytic mechanism of the EHs. Although the overall EH mechanism is now known, the molecular basis of substrate selectivity, possible allosteric regulation, and many fine details of the catalytic mechanism remain to be solved. Finally, recent development in the design of EH inhibitors and the EH biological role are discussed.

scholarly journals Design of a de novo aggregating antimicrobial peptide and bacterial conjugation delivery system

2018 ◽  
Author(s):  
Logan T. Collins ◽  
Peter B. Otoupal ◽  
Colleen M. Courtney ◽  
Anushree Chatterjee
Keyword(s):  
Antibiotic Resistance ◽  
Antimicrobial Peptides ◽  
Antimicrobial Peptide ◽  
Rational Design ◽  
De Novo ◽  
Protein Aggregates ◽  
Conjugative Plasmid ◽  
Design Parameters ◽  
Bacterial Conjugation ◽  
Artificial Gene

AbstractTraditional antibiotics are reaching obsolescence as a consequence of antibiotic resistance; therefore novel antibiotic approaches are needed. A recent non-traditional approach involves formation of protein aggregates as antimicrobials to disrupt bacterial homeostasis. Previous work on protein aggregates has focused on genome mining for aggregation-prone sequences in bacterial genomes rather than on rational design of aggregating antimicrobial peptides. Here, we use a synthetic biology approach to design an artificial gene encoding the first de novo aggregating antimicrobial peptide. This artificial gene,opaL(overexpressed protein aggregator Lipophilic), disrupts bacterial homeostasis by expressing extremely hydrophobic peptides. When this hydrophobic sequence is disrupted by acidic residues, consequent aggregation and antimicrobial effect decreases. Further, to deliver this artificial gene, we developed a probiotic approach using RK2, a broad host range conjugative plasmid, to transferopaLfrom donor to recipient bacteria. We utilize RK2 to mobilize a shuttle plasmid carrying theopaLgene by adding the RK2 origin of transfer. We show thatopaLis non-toxic to the donor, allowing for maintenance and transfer since its expression is under control of a promoter with a recipient-specific T7 RNA polymerase. Upon mating of donor and recipientEscherichia coli, we observe selective growth repression in T7 polymerase expressing recipients. This technique could be used to target desired pathogens by selecting pathogen-specific promoters to controlopaLexpression. This system provides a basis for the design and delivery of novel antimicrobial peptides.ImportanceThe growing threat of antibiotic resistance necessitates new treatment options for bacterial infections that are recalcitrant to traditional antimicrobials. Existing methods usually involve small-molecule compounds which interfere with essential processes in bacterial cells. By contrast, protein aggregates operate by causing widespread disruption of bacterial homeostasis and may provide a new method for combating infections. We used rational design to create and test an aggregating de novo antimicrobial peptide, OpaL. In addition, we employed bacterial conjugation to deliver theopaLgene from donor bacteria to recipient bacteria while using a strain-specific promoter to ensure that OpaL was only expressed in targeted recipients. To the best of our knowledge, this represents the first design for a de novo peptide with aggregation-mediated antimicrobial activity. We envision that OpaL’s design parameters could be used in developing a new class of antimicrobial peptides to help treat antibiotic resistant infections.

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