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Pels Charitable Trust to The Rockefeller University","award":["Postdoctoral Fellowship"],"award-info":[{"award-number":["Postdoctoral Fellowship"]}]},{"name":"NIH\/NIGMS","award":["R01 GM38330"],"award-info":[{"award-number":["R01 GM38330"]}]},{"name":"NIH\/NIGMS","award":["R35 GM151879"],"award-info":[{"award-number":["R35 GM151879"]}]},{"name":"NIH\/NIGMS","award":["R35 GM118130"],"award-info":[{"award-number":["R35 GM118130"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,7,7]]},"abstract":"<jats:p>\n                    The nucleotide addition cycle (NAC) of multisubunit DNA-dependent RNA polymerases (RNAPs) involves coordinated conformational changes in conserved active-site structural elements, including the trigger loop (TL). The TL is open (unfolded) in most RNAP structures but can close (fold) in substrate-bound (post- or pretranslocated) states of the RNAP, promoting catalysis. TL closure has been associated with closure of another conserved structural element, the Rim-Helices\/F-loop (RH-FL), but the role of the RH-FL in the NAC is unclear. Antibiotic leads CBR9379 and AAP-SO\n                    <jats:sub>2<\/jats:sub>\n                    inhibit the\n                    <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                    RNAPs, respectively, by binding in a pocket formed by the bridge helix and RH-FL. The precise mechanism of action for these inhibitors is yet to be defined. We present cryoelectron microscopy structures showing that both compounds inhibit the RNAP NAC by preventing RH-FL closure, thereby allosterically destabilizing the closed TL. This work reveals a conserved mechanistic principle of RNAP catalysis across all domains of life and provides insight for antibiotic design.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2609228123","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T17:43:55Z","timestamp":1782841435000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["RNA polymerase inhibitors reveal active-site motions essential for the nucleotide addition cycle"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9060-8201","authenticated-orcid":false,"given":"Yukti","family":"Dhingra","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0420db125","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Biophysics, The Rockefeller University","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5042-0383","authenticated-orcid":false,"given":"Robert","family":"Landick","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Wisconsin","place":["Madison"]},{"name":"Department of Bacteriology, University of Wisconsin","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1332-128X","authenticated-orcid":false,"given":"Elizabeth A.","family":"Campbell","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0420db125","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Pathogenesis, The Rockefeller University","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8241-3153","authenticated-orcid":false,"given":"Seth A.","family":"Darst","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0420db125","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Biophysics, The Rockefeller University","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"e_1_3_4_1_2","first-page":"206","volume-title":"RNA Polymerases as Molecular Motors","author":"Zhang J.","unstructured":"J. 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