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dc.contributorDepartment of Applied Biology and Chemical Technologyen_US
dc.contributorChinese Mainland Affairs Officeen_US
dc.creatorHuang, Len_US
dc.creatorSo, PKen_US
dc.creatorChen, YWen_US
dc.creatorLeung, YCen_US
dc.creatorYao, ZPen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen_US
dc.rights© 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CCBY license (
dc.rightsThe following publication Huang, L., So, P. K., Chen, Y. W., Leung, Y. C., & Yao, Z. P. (2021). Interdomain flexibility and interfacial integrity of β-lactamase inhibitory protein (BLIP) modulate its binding to class A β-lactamases. Journal of Biological Chemistry, 297(2) is available at
dc.subjectβ-lactamase inhibitory protein (BLIP)en_US
dc.subjectInterdomain flexibilityen_US
dc.subjectInterfacial integrityen_US
dc.subjectHydrogen deuterium exchange mass spectrometryen_US
dc.subjectMolecular dynamics simulationen_US
dc.titleInterdomain flexibility and interfacial integrity of β-lactamase inhibitory protein (BLIP) modulate its binding to class A β-lactamasesen_US
dc.typeJournal/Magazine Articleen_US
dcterms.abstractβ-Lactamase inhibitory protein (BLIP) consists of a tandem repeat of αβ domains conjugated by an interdomain loop and can effectively bind and inactivate class A β-lactamases, which are responsible for resistance of bacteria to β-lactam antibiotics. The varied ability of BLIP to bind different β-lactamases and the structural determinants for significant enhancement of BLIP variants with a point mutation are poorly understood. Here, we investigated the conformational dynamics of BLIP upon binding to three clinically prevalent class A β-lactamases (TEM1, SHV1, and PC1) with dissociation constants between subnanomolar and micromolar. Hydrogen deuterium exchange mass spectrometry revealed that the flexibility of the interdomain region was significantly suppressed upon strong binding to TEM1, but was not significantly changed upon weak binding to SHV1 or PC1. E73M and K74G mutations in the interdomain region improved binding affinity toward SHV1 and PC1, respectively, showing significantly increased flexibility of the interdomain region compared to the wild-type and favorable conformational changes upon binding. In contrast, more rigidity of the interfacial loop 135-145 was observed in these BLIP mutants in both free and bound states. Consistently, molecular dynamics simulations of BLIP exhibited drastic changes in the flexibility of the loop 135-145 in all complexes. Our results indicated for the first time that higher flexibility of the interdomain linker, as well as more rigidity of the interfacial loop 135-145, could be desirable determinants for enhancing inhibition of BLIP to class A β-lactamases. Together, these findings provide unique insights into the design of enhanced inhibitors.en_US
dcterms.accessRightsopen accessen_US
dcterms.bibliographicCitationJournal of biological chemistry, Aug. 2021, v. 297, no. 2, 100980en_US
dcterms.isPartOfJournal of biological chemistryen_US
dc.description.validate202202 bcvcen_US
dc.description.oaVersion of Recorden_US
dc.identifier.FolderNumberRGC-B1-134b, OA_Scopus/WOS-
dc.description.fundingTextThis work was supported by Hong Kong Research Grants Council (Grant Nos. 153040/15P, 153348/16P, 153041/17P, 15304020, R5013-19F, C5031-14E, C4002-17G, and R4005-18), Natural Science Foundation of China (Grant No. 81874306), and China Resources Life Sciences Group Limited.en_US
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