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Recently, a transferable gene cluster\n              <jats:italic>tmexCD1-toprJ1<\/jats:italic>\n              of the resistance-nodulation-division (RND) superfamily was identified in the plasmids of animal-derived\n              <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n              strains, with a higher efflux capacity for various drugs than the\n              <jats:italic>Escherichia coli<\/jats:italic>\n              AcrAB-TolC homolog system. In this study, we focused on the differences in the inner membrane pump of these two systems and identified some key residues that contribute to the robust efflux activity of the TMexCD1 system. With the aid of homologous modeling and molecular docking, eight residues from the proximal binding pocket (PBP) and nine from the distal binding pocket (DBP) were selected and subjected to site-directed mutagenesis. Several of them, such as S134, I139, D181, and A290, were shown to be important for substrate binding in the DBP region, and all residues in PBP and DBP showed certain substrate preferences. Apart from the conservative switch loop (L613\u2013623\n              <jats:sup>TMexD1<\/jats:sup>\n              ) previously identified in the\n              <jats:italic>E. coli<\/jats:italic>\n              AcrB (EcAcrB), a relatively unconservative loop (L665\u2013675\n              <jats:sup>TMexD1<\/jats:sup>\n              ) at the bottom of PBP was proposed as a critical element for the robust activity of TMexD1, due to variations at sites E669, G670, N673, and S674 compared to EcAcrAB, and the significantly altered efflux activity due to their mutations. The conservation and flexibility of these key factors can contribute to the evolution of the RND efflux pumps and thus serve as potential targets for developing inhibitors to block the widespread of the TMexCD1 system.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/aac.01678-23","type":"journal-article","created":{"date-parts":[[2024,3,17]],"date-time":"2024-03-17T17:19:19Z","timestamp":1710695959000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Deciphering the molecular and functional basis of TMexCD1: the plasmid-encoded efflux pump of resistance-nodulation-division superfamily"],"prefix":"10.1128","volume":"68","author":[{"given":"Yan","family":"Shang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao, China"},{"name":"Poultry Institute, Shandong Academy of Agricultural Sciences, 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Sciences, Shandong University, Jinan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanxiang","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chongzhou","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luhua","family":"Feng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Honglei","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Technology, Institute 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