Gating interactions steer loop conformational changes in the active site of the L1 metallo-β-lactamase

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dc.citation.titleeLife
dc.contributor.orcidhttp://orcid.org/0000-0002-1380-9824
dc.contributor.orcidhttp://orcid.org/0000-0001-7770-9091
dc.contributor.orcidhttp://orcid.org/0000-0002-7978-3233
dc.contributor.orcidhttp://orcid.org/0000-0003-2650-2925
dc.creatorZhao, Zhuoran
dc.creatorShen, Xiayu
dc.creatorChen, Shuang
dc.creatorGu, Jing
dc.creatorWang, Haun
dc.creatorMojica, María F.
dc.creatorSamanta, Moumita
dc.creatorBhowmik, Debsindhu
dc.creatorVila, Alejandro J.
dc.creatorBonomo, Robert A.
dc.creatorHaider, Shozeb
dc.date.accessioned2024-09-19T16:25:26Z
dc.date.available2024-09-19T16:25:26Z
dc.date.issued2023-02-24
dc.description.abstractβ-Lactam antibiotics are the most important and widely used antibacterial agents across the world. However, the widespread dissemination of β-lactamases among pathogenic bacteria limits the efficacy of β-lactam antibiotics. This has created a major public health crisis. The use of β-lactamase inhibitors has proven useful in restoring the activity of β-lactam antibiotics, yet, effective clinically approved inhibitors against class B metallo-β-lactamases are not available. L1, a class B3 enzyme expressed by Stenotrophomonas maltophilia, is a significant contributor to the β-lactam resistance displayed by this opportunistic pathogen. Structurally, L1 is a tetramer with two elongated loops, α3-β7 and β12-α5, present around the active site of each monomer. Residues in these two loops influence substrate/inhibitor binding. To study how the conformational changes of the elongated loops affect the active site in each monomer, enhanced sampling molecular dynamics simulations were performed, Markov State Models were built, and convolutional variational autoencoder-based deep learning was applied. The key identified residues (D150a, H151, P225, Y227, and R236) were mutated and the activity of the generated L1 variants was evaluated in cellbased experiments. The results demonstrate that there are extremely significant gating interactions between α3-β7 and β12-α5 loops. Taken together, the gating interactions with the conformational changes of the key residues play an important role in the structural remodeling of the active site. These observations offer insights into the potential for novel drug development exploiting these gating interactions.
dc.description.filFil: Zhao, Zhuoran. University College London. School of Pharmacy. Department of Pharmaceutical and Biological Chemistry; United Kingdom.
dc.description.filFil: Shen, Xiayu. University College London. School of Pharmacy. Department of Pharmaceutical and Biological Chemistry; United Kingdom.
dc.description.filFil: Chen, Shuang. University College London. School of Pharmacy. Department of Pharmaceutical and Biological Chemistry; United Kingdom.
dc.description.filFil: Gu, Jing. University College London. School of Pharmacy. Department of Pharmaceutical and Biological Chemistry; United Kingdom.
dc.description.filFil: Wang, Haun. University College London. School of Pharmacy. Department of Pharmaceutical and Biological Chemistry; United Kingdom.
dc.description.filFil: Mojica, María F. Case Western Reserve University School of Medicine. Department of Molecular Biology and Microbiology; United States.
dc.description.filFil: Mojica, María F. Louis Stokes Cleveland Department of Veterans Affairs Medical Center; United States.
dc.description.filFil: Mojica, María F. CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology; United States.
dc.description.filFil: Samanta, Moumita. Georgia Institute of Technology. College of Computing; United States.
dc.description.filFil: Bhowmik, Debsindhu. Oak Ridge National Laboratories. Computer Science and Engineering Division; United States.
dc.description.filFil: Vila, Alejandro J. CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology; United States.
dc.description.filFil: Vila, Alejandro J. Instituto de Biología Molecular y Celular de Rosario. Laboratorio de Metaloproteínas; Argentina.
dc.description.filFil: Vila, Alejandro J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Área Biofísica; Argentina.
dc.description.filFil: Bonomo, Robert A. Case Western Reserve University School of Medicine. Department of Molecular Biology and Microbiology; United States.
dc.description.filFil: Bonomo, Robert A. Louis Stokes Cleveland Department of Veterans Affairs Medical Center; United States.
dc.description.filFil: Bonomo, Robert A. CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology; United States.
dc.description.filFil: Bonomo, Robert A. Case Western Reserve University School of Medicine. Departments of Medicine, Biochemistry, Pharmacology, and Proteomics and Bioinformatics; United States.
dc.description.filFil: Haider, Shozeb. University College London. School of Pharmacy. Department of Pharmaceutical and Biological Chemistry; United Kingdom.
dc.description.filFil: Haider, Shozeb. University College London. UCL Centre for Advanced Research Computing; United Kingdom.
dc.description.sponsorshipNational Institutes of Health: R01AI100560
dc.description.sponsorshipUS CDC Prevention Epicenters Program: U54CK000603
dc.format.extent1-18
dc.identifier.issn2050-084X
dc.identifier.urihttps://hdl.handle.net/2133/27832
dc.language.isoen
dc.publishereLife Sciences Publications
dc.relation.publisherversionhttps://doi.org/10.7554/eLife.83928
dc.relation.publisherversionhttps://elifesciences.org/articles/83928
dc.rightsopenAccess
dc.rights.holderZhao, Zhuoran
dc.rights.holderShen, Xiayu
dc.rights.holderChen, Shuang
dc.rights.holderGu, Jing
dc.rights.holderWang, Haun
dc.rights.holderMojica, María F.
dc.rights.holderSamanta, Moumita
dc.rights.holderBhowmik, Debsindhu
dc.rights.holderVila, Alejandro J.
dc.rights.holderBonomo, Robert A.
dc.rights.holderHaider, Shozeb
dc.rights.holderUniversidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas
dc.rights.textAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectInhibidores de beta-Lactamasas
dc.subjectbeta-Lactamasas
dc.subjectFarmacorresistencia Microbiana
dc.subjectCatalytic Domain
dc.titleGating interactions steer loop conformational changes in the active site of the L1 metallo-β-lactamase
dc.typearticulo
dc.type.collectionarticulo
dc.type.versionpublishedVersion

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