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primary topic: Insights into dynamic changes in ADC-7 and P99 cephalosporinases using small angle x-ray scattering (SAXS)

Insights into dynamic changes in ADC-7 and P99 cephalosporinases using small angle x-ray scattering (SAXS)
type: AcademicArticle
type: Article
abstract: To counter the emergence of β-lactamase (BL) mediated resistance, design of new β-lactamase inhibitors (BLIs) is critical. Many high-resolution crystallographic structures of BL complexed with BLIs are available. However, their impact on BLI design is struggling to keep pace with novel and emerging variants. Small angle x-ray scattering (SAXS) in combination with molecular modeling is a useful tool to determine dynamic structures of macromolecules in solution. An important application of SAXS is to determine the conformational changes that occur when BLI bind to BL. To probe if conformational dynamics occur in class C cephalosporinases, we studied SAXS profiles of two clinically relevant class C β-lactamases, Acinetobacter baumannii ADC-7 and Enterobacter cloacae P99 in apo format complexed with BLIs. Importantly, SAXS data analysis demonstrated that in solution, these representative class C enzymes remain monomeric and did not show the associated assemblies that were seen in various crystal structures. SAXS data acquired for ADC-7 and P99, in apo and inhibitor bound states, clearly showed that these enzymes undergo detectable conformational changes, and these class C β-lactamases also close upon binding inhibitors as does BlaC. Further analysis revealed that addition of inhibitor led to the compacting of a range of residues around the active site, indicating that the conformational changes that both P99 and ADC-7 undergo are central to inhibitor recognition and efficacy. Our findings support the importance of exploring conformational changes using SAXS analysis in the design of future BLIs.
date: 2023-08
volume: 14
is part of: Journal of Biomolecular Structure and Dynamics
status: peerReviewed
status: published
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository
subject: QR Microbiology

Adenine Press
type: Organization

Journal of Biomolecular Structure and Dynamics
type: Collection
issn: 07391102

Andrea M Hujer
type: Person
given name: Andrea M
family name: Hujer

Kanika Dhiman
type: Person
given name: Kanika
family name: Dhiman

Robert A Bonomo
type: Person
given name: Robert A
family name: Bonomo

Ish Kumar
type: Person
given name: Ish
family name: Kumar

Ashish .
type: Person
given name: Ashish
family name: .

Justin Carifi
type: Person
given name: Justin
family name: Carifi

Christopher R Bethel
type: Person
given name: Christopher R
family name: Bethel

Amin Sagar
type: Person
given name: Amin
family name: Sagar

HTML Summary of #3186 Insights into dynamic changes in ADC-7 and P99 cephalosporinases using small angle x-ray scattering (SAXS)
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primary topic: Insights into dynamic changes in ADC-7 and P99 cephalosporinases using small angle x-ray scattering (SAXS)

QR Microbiology
type: Concept