{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:26:23Z","timestamp":1790166383981,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2016,5,25]],"date-time":"2016-05-25T00:00:00Z","timestamp":1464134400000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2016,5,25]],"date-time":"2016-05-25T00:00:00Z","timestamp":1464134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006224","name":"Argonne National Laboratory","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006224","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004948","name":"Michigan Economic Development Corporation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004948","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["MCB 1024945"],"award-info":[{"award-number":["MCB 1024945"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                      is a human respiratory pathogen that causes the deadly disease tuberculosis. The rapid global spread of antibiotic\u2010resistant\n                      <jats:italic>M. tuberculosis<\/jats:italic>\n                      makes tuberculosis infections difficult to treat. To overcome this problem new effective antimicrobial strategies are urgently needed. One promising target for new therapeutic approaches is PonA1, a class A penicillin\u2010binding protein, which is required for maintaining physiological cell wall synthesis and cell shape during growth in mycobacteria. Here, crystal structures of the transpeptidase domain, the enzymatic domain responsible for penicillin binding, of PonA1 from\n                      <jats:italic>M. tuberculosis<\/jats:italic>\n                      in the inhibitor\u2010free form and in complex with penicillin V are reported. We used site\u2010directed mutagenesis, antibiotic profiling experiments, and fluorescence thermal shift assays to measure PonA1's sensitivity to different classes of \u03b2\u2010lactams. Structural comparison of the PonA1 apo\u2010form and the antibiotic\u2010bound form shows that binding of penicillin V induces conformational changes in the position of the loop \u03b24\u2032\u2010\u03b13 surrounding the penicillin\u2010binding site. We have also found that binding of different antibiotics including penicillin V positively impacts protein stability, while other tested \u03b2\u2010lactams such as clavulanate or meropenem resulted in destabilization of PonA1. Our antibiotic profiling experiments indicate that the transpeptidase activity of PonA1 in both\n                      <jats:italic>M. tuberculosis<\/jats:italic>\n                      and\n                      <jats:italic>M. smegmatis<\/jats:italic>\n                      mediates tolerance to specific cell wall\u2010targeting antibiotics, particularly to penicillin V and meropenem. Because\n                      <jats:italic>M. tuberculosis<\/jats:italic>\n                      is an important human pathogen, these structural data provide a template to design novel transpeptidase inhibitors to treat tuberculosis infections.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Database<\/jats:title>\n                    <jats:p>\n                      Structural data are available in the PDB database under the accession numbers\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.rcsb.org\/pdb\/search\/structidSearch.do?structureId=5CRF\">5CRF<\/jats:ext-link>\n                      and\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.rcsb.org\/pdb\/search\/structidSearch.do?structureId=5CXW\">5CXW<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/febs.13738","type":"journal-article","created":{"date-parts":[[2016,4,22]],"date-time":"2016-04-22T18:23:46Z","timestamp":1461349426000},"page":"2206-2218","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Crystal structures of the transpeptidase domain of the\n                    <i>Mycobacterium tuberculosis<\/i>\n                    penicillin\u2010binding protein PonA1 reveal potential mechanisms of antibiotic resistance"],"prefix":"10.1111","volume":"283","author":[{"given":"Ekaterina V.","family":"Filippova","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics Feinberg School of Medicine Northwestern University Chicago IL USA"},{"name":"Midwest Center for Structural Genomics (MCSG) Biosciences Division Argonne National Laboratory Argonne, IL USA"},{"name":"Center for Structural Genomics of Infectious Diseases (CSGID) Feinberg School of Medicine Northwestern University Chicago, IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen J.","family":"Kieser","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Disease Harvard T.H. Chan School of Public Health Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi\u2010Hao","family":"Luan","sequence":"additional","affiliation":[{"name":"Midwest Center for Structural Genomics (MCSG) Biosciences Division Argonne National Laboratory Argonne, IL USA"},{"name":"High Throughput Analysis Laboratory and Department of Molecular Biosciences Northwestern University Evanston IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zdzislaw","family":"Wawrzak","sequence":"additional","affiliation":[{"name":"Life Science Collaborative Access Team Synchrotron Research Center Northwestern University Evanston IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Kiryukhina","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics Feinberg School of Medicine Northwestern University Chicago IL USA"},{"name":"Midwest Center for Structural Genomics (MCSG) Biosciences Division Argonne National Laboratory Argonne, IL USA"},{"name":"Center for Structural Genomics of Infectious Diseases (CSGID) Feinberg School of Medicine Northwestern University Chicago, IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J.","family":"Rubin","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Disease Harvard T.H. Chan School of Public Health Boston MA USA"},{"name":"Department of Microbiology and Immunobiology Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne F.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics Feinberg School of Medicine Northwestern University Chicago IL USA"},{"name":"Midwest Center for Structural Genomics (MCSG) Biosciences Division Argonne National Laboratory Argonne, IL USA"},{"name":"Center for Structural Genomics of Infectious Diseases (CSGID) Feinberg School of Medicine Northwestern University Chicago, IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,5,25]]},"reference":[{"key":"e_1_2_9_2_1","volume-title":"Global Tuberculosis Report 2014","author":"World Health 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