Structural Determination of Putative Lytic Transglycoslyase Inhibitor IVY-P2 through X-Ray Crystallography
Disciplines
Biochemistry | Other Biochemistry, Biophysics, and Structural Biology | Structural Biology
Abstract (300 words maximum)
Pseudomonas aeruginosa is a pathogenic Gram-negative bacterium with the potential to cause serious illnesses, notably lung infections in immunocompromised individuals. The formation of biofilms and pervasive multiple drug-resistant strains, makes treatment of P. aeruginosa with traditional antibiotics difficult. Therefore, research into potential drug targets and development of novel treatment options are of paramount importance for controlling deadly infections. One potential drug target, IvyP2, is a homolog of lysozyme glycoside hydrolase inhibitor IvyP1 and is purported to be an inhibitor of P. aeruginosa lytic transglycosylases. While the structure of Ivyp1 is known (Abergel) and the structure of Ivyp2 is not, there are conflicting observations about the mechanisms for molecular recognition in this family. To define the details of molecular recognition that govern specificity and potency, the structure of Ivyp2 was studied to enable comparison to structures of Ivyp1. A structure of Ivyp2 determined by X-ray crystallography revealed significant structural homology with notable divergence at the N-terminal alpha helix between Ivyp1 and Ivyp2. While prior structural work on Ivyp1 suggests that the key inactivation loop is the predominant driver for molecular recognition, our data suggests that additional surface contacts are required. A thorough understanding of the specifics of molecular recognition within the IVY family may answer some of the persistent questions regarding peptidoglycan synthesis and remodeling.
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Academic department under which the project should be listed
CSM – Chemistry and Biochemistry
Primary Investigator (PI) Name
Thomas Leeper
Structural Determination of Putative Lytic Transglycoslyase Inhibitor IVY-P2 through X-Ray Crystallography
Pseudomonas aeruginosa is a pathogenic Gram-negative bacterium with the potential to cause serious illnesses, notably lung infections in immunocompromised individuals. The formation of biofilms and pervasive multiple drug-resistant strains, makes treatment of P. aeruginosa with traditional antibiotics difficult. Therefore, research into potential drug targets and development of novel treatment options are of paramount importance for controlling deadly infections. One potential drug target, IvyP2, is a homolog of lysozyme glycoside hydrolase inhibitor IvyP1 and is purported to be an inhibitor of P. aeruginosa lytic transglycosylases. While the structure of Ivyp1 is known (Abergel) and the structure of Ivyp2 is not, there are conflicting observations about the mechanisms for molecular recognition in this family. To define the details of molecular recognition that govern specificity and potency, the structure of Ivyp2 was studied to enable comparison to structures of Ivyp1. A structure of Ivyp2 determined by X-ray crystallography revealed significant structural homology with notable divergence at the N-terminal alpha helix between Ivyp1 and Ivyp2. While prior structural work on Ivyp1 suggests that the key inactivation loop is the predominant driver for molecular recognition, our data suggests that additional surface contacts are required. A thorough understanding of the specifics of molecular recognition within the IVY family may answer some of the persistent questions regarding peptidoglycan synthesis and remodeling.