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However, the widespread dissemination of \u03b2-lactamases among pathogenic bacteria limits the efficacy of \u03b2-lactam antibiotics. This has created a major public health crisis. The use of \u03b2-lactamase inhibitors has proven useful in restoring the activity of \u03b2-lactam antibiotics, yet, effective clinically approved inhibitors against class B metallo-\u03b2-lactamases are not available. L1, a class B3 enzyme expressed by\n                    <jats:italic>Stenotrophomonas maltophilia<\/jats:italic>\n                    , is a significant contributor to the \u03b2-lactam resistance displayed by this opportunistic pathogen. Structurally, L1 is a tetramer with two elongated loops, \u03b13-\u03b27 and \u03b212-\u03b15, 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 cell-based experiments. The results demonstrate that there are extremely significant gating interactions between \u03b13-\u03b27 and \u03b212-\u03b15 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.\n                  <\/jats:p>","DOI":"10.7554\/elife.83928","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T07:15:28Z","timestamp":1675667728000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.83928","source":"Crossref","is-referenced-by-count":10,"title":["Gating interactions steer loop conformational changes in the active site of the L1 metallo-\u03b2-lactamase"],"prefix":"10.7554","volume":"12","author":[{"given":"Zhuoran","family":"Zhao","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jx3x895","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, University College London","place":["London, United 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