dc.contributor.author
Schneider, Samuel H.
dc.contributor.author
Kozuch, Jacek
dc.contributor.author
Boxer, Steven G.
dc.date.accessioned
2022-02-28T10:27:00Z
dc.date.available
2022-02-28T10:27:00Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/34217
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-33935
dc.description.abstract
The interplay of enzyme active site electrostatics and chemical positioning is important for understanding the origin(s) of enzyme catalysis and the design of novel catalysts. We reconstruct the evolutionary trajectory of TEM-1 β-lactamase to TEM-52 toward extended-spectrum activity to better understand the emergence of antibiotic resistance and to provide insights into the structure–function paradigm and noncovalent interactions involved in catalysis. Utilizing a detailed kinetic analysis and the vibrational Stark effect, we quantify the changes in rates and electric fields in the Michaelis and acyl-enzyme complexes for penicillin G and cefotaxime to ascertain the evolutionary role of electric fields to modulate function. These data are combined with MD simulations to interpret and quantify the substrate-dependent structural changes during evolution. We observe that this evolutionary trajectory utilizes a large preorganized electric field and substrate-dependent chemical positioning to facilitate catalysis. This governs the evolvability, substrate promiscuity, and protein fitness landscape in TEM β-lactamase antibiotic resistance.
en
dc.format.extent
13 Seiten
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject
Electric fields
en
dc.subject
Peptides and proteins
en
dc.subject.ddc
500 Naturwissenschaften und Mathematik::540 Chemie::540 Chemie und zugeordnete Wissenschaften
dc.title
The Interplay of Electrostatics and Chemical Positioning in the Evolution of Antibiotic Resistance in TEM β-Lactamases
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.doi
10.1021/acscentsci.1c00880
dcterms.bibliographicCitation.journaltitle
ACS Central Science
dcterms.bibliographicCitation.number
12
dcterms.bibliographicCitation.pagestart
1996
dcterms.bibliographicCitation.pageend
2008
dcterms.bibliographicCitation.volume
7
dcterms.bibliographicCitation.url
https://doi.org/10.1021/acscentsci.1c00880
refubium.affiliation
Physik
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.isPartOf.eissn
2374-7951
refubium.resourceType.provider
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