In Silico Docking of Small-Molecule Inhibitors to the Escherichia coli Type III Secretion System EscN ATPase

The type III secretion system (T3SS) is a supermolecular construct that allows many Gram-negative pathogens to translocate effector virulence proteins directly into host cells in a process requiring adenosine triphosphate (ATP) hydrolysis. We used in silico molecular modeling and computational chemi...

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Bibliographic Details
Main Authors: Henderson, Terry J, Carmany, Daniel O
Format: Report
Language:English
Subjects:
ADENOSINE PHOSPHATES
Anatomy and Physiology
ATPASE(ADENOSINE TRIPHOSPHATASE)
BROAD-SPECTRUM ANTIBIOTIC
BROADBAND
CATALYSTS
CELLS(BIOLOGY)
COMPUTATIONAL CHEMISTRY
DRUG DISCOVERY
ENTEROPATHOGENS
ENZYME INHIBITORS
ENZYME STRUCTURE
ESCHERICHIA COLI
HOSTS(BIOLOGY)
HYDROGEN BONDS
INJECTOSOME
LEAD COMPOUNDS
Microbiology
MOLECULAR MODELING
PATHOGENIC MICROORGANISMS
PROTEIN DOCKING
PROTEINS
SECRETION
TYPE III SECRETION SYSTEM
VIRULENCE
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Summary:The type III secretion system (T3SS) is a supermolecular construct that allows many Gram-negative pathogens to translocate effector virulence proteins directly into host cells in a process requiring adenosine triphosphate (ATP) hydrolysis. We used in silico molecular modeling and computational chemistry to determine the conformations of three different small-molecule compounds when bound to EscN, the T3SS ATPase of enteropathogenic Escherichia coli. Each compound was shown to separately bind EscN within or very close to its active site and to effectively inhibit catalytic activity. Two structurally related compounds were observed to adopt extended conformations in the active-site cleft and essentially occupied the entire cleft, which obstructed the ATP binding including the formation of ATP-EscN non-covalent interactions and hydrogen bonds. Both compounds appeared to span the region in the active site with Phe355 and Gln426, residues that are essential for forming -stacking interactions and hydrogen bonds with the adenosine base of the ATP substrate. In contrast, the third compound appeared to fold upon itself in the EscN active-site cleft to adopt a very compact conformation that occupied only one side of the cleft. Our goal was to determine the three-dimensional structures of the compound EscN complexes for designing lead compounds and ultimately develop broad-spectrum therapeutics against T3SS pathogens. The original document contains color images.