DC FieldValueLanguage
dc.contributorDepartment of Applied Biology and Chemical Technologyen_US
dc.contributorUniversity Research Facility in Life Sciencesen_US
dc.creatorHuang, Len_US
dc.creatorSo, PKen_US
dc.creatorChen, YWen_US
dc.creatorLeung, YCen_US
dc.creatorYao, ZPen_US
dc.date.accessioned2021-05-13T08:31:55Z-
dc.date.available2021-05-13T08:31:55Z-
dc.identifier.issn0002-7863en_US
dc.identifier.urihttp://hdl.handle.net/10397/89872-
dc.language.isoenen_US
dc.publisherAmerican Chemical Societyen_US
dc.titleConformational dynamics of the helix 10 region as an allosteric site in class A β-lactamase Inhibitory bindingen_US
dc.typeJournal/Magazine Articleen_US
dc.identifier.spage13756en_US
dc.identifier.epage13767en_US
dc.identifier.volume142en_US
dc.identifier.issue32en_US
dc.identifier.doi10.1021/jacs.0c04088en_US
dcterms.abstractβ-Lactamase inhibitory protein (BLIP) can effectively inactivate class A β-lactamases, but with very different degrees of potency. Understanding the different roles of BLIP in class A β-lactamases inhibition can provide insights for inhibitor design. However, this problem was poorly solved on the basis of the static structures obtained by X-ray crystallography. In this work, ion mobility mass spectrometry, hydrogen-deuterium exchange mass spectrometry, and molecular dynamics simulation revealed the conformational dynamics of three class A β-lactamases with varying inhibition efficiencies by BLIP. A more extended conformation of PC1 was shown compared to those of TEM1 and SHV1. Localized dynamics differed in several important loop regions, that is, the protruding loop, H10 loop, ω loop, and SDN loop. Upon binding with BLIP, these loops cooperatively rearranged to enhance the binding interface and to inactivate the catalytic sites. In particular, unfavorable changes in conformational dynamics were found in the protruding loop of SHV1 and PC1, showing less effective binding. Intriguingly, the single mutation on BLIP could compensate for the unfavored changes in this region, and thus exhibit enhanced inhibition toward SHV1 and PC1. Additionally, the H10 region was revealed as an important allosteric site that could modulate the inhibition of class A β-lactamases. It was suggested that the rigid protruding loop and flexible H10 region might be determinants for the effective inhibition of TEM1. Our findings provided unique and explicit insights into the conformational dynamics of β-lactamases and their bindings with BLIP. This work can be extended to other β-lactamases of interest and inspire the design of novel inhibitors. Copyrighten_US
dcterms.accessRightsembargoed accessen_US
dcterms.bibliographicCitationJournal of the American Chemical Society, 12 Aug. 2020, v. 142, no. 32, p. 13756-13767en_US
dcterms.isPartOfJournal of the American Chemical Societyen_US
dcterms.issued2020-08-
dc.identifier.scopus2-s2.0-85089611783-
dc.identifier.pmid32686406-
dc.identifier.eissn1520-5126en_US
dc.description.validate202105 bchyen_US
dc.description.oaNot applicableen_US
dc.identifier.FolderNumbera0762-n02-
dc.identifier.SubFormID1475-
dc.description.fundingSourceRGCen_US
dc.description.fundingTextCouncil (Nos. 153040/15P, 153348/16P, 153041/17P, C5031 14E R4005 18 and C4002 17Gen_US
dc.description.pubStatusPublisheden_US
dc.date.embargo2021.08.31en_US
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