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Phosphofructokinase-1 (PFK), the highly conserved, rate-limiting glycolytic enzyme, is a paradigm for Monod\u2013Wyman\u2013Changeux allosteric kinetics. However, X-ray crystal structures of bacterial PFK orthologs in distinct ligand-bound states do not show the consistent, concerted structural rearrangements expected for classical \u201crelaxed\u201d and \u201ctense\u201d states, revealing a decades-long disconnect between structure and function. We resolve this paradox by integrating biophysical and computational approaches to show that activator and inhibitor binding to the same allosteric pocket differentially reweight the conformational ensemble of Escherichia coli PFK. Activator binding enriches conformational substates that preorganize the catalytic site, whereas inhibitor binding upweights apo-like, catalytically incompetent substates. These findings establish an ensemble-based mechanism for PFK regulation and provide an energetic framework for understanding the expanded allosteric architecture of eukaryotic PFK orthologs.<\/jats:p>","DOI":"10.1021\/jacs.6c08065","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T06:02:02Z","timestamp":1787032922000},"page":"36754-36769","source":"Crossref","is-referenced-by-count":0,"title":["Bidirectional Allosteric\nLigand Regulation in a Central\nGlycolytic Enzyme"],"prefix":"10.1021","volume":"148","author":[{"given":"Belen","family":"Sundberg","sequence":"first","affiliation":[{"name":"Columbia University , , , ,","place":["New York, New York, United States, 10032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenlin","family":"Lu","sequence":"additional","affiliation":[{"name":"Columbia University , , , ,","place":["New York, New York, United States, 10032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malcolm L.","family":"Wells","sequence":"additional","affiliation":[{"name":"Columbia University , , , ,","place":["New York, New York, United States, 10032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle C.","family":"Weber","sequence":"additional","affiliation":[{"name":"Columbia University , , , ,","place":["New York, New York, United States, 10032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Gong","sequence":"additional","affiliation":[{"name":"Columbia University , , , ,","place":["New York, New York, United States, 10032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0938-881X","authenticated-orcid":true,"given":"Anum","family":"Glasgow","sequence":"additional","affiliation":[{"name":"Columbia University , , , ,","place":["New York, New York, United States, 10032"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"2026090312084251100_cit1","first-page":"159","article-title":"Protein structure and function","volume":"262","author":"Berg","year":"2002","journal-title":"Biochemistry"},{"key":"2026090312084251100_cit2","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1038\/309467a0","article-title":"Evolution\nof phosphofructokinase\u2500gene duplication and creation of new\neffector sites","volume":"309","author":"Poorman","year":"1984","journal-title":"Nature"},{"key":"2026090312084251100_cit3","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/0014-5793(68)80115-2","article-title":"Phosphofructokinase\nfrom E. 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Mol.\nMed."},{"key":"2026090312084251100_cit6","doi-asserted-by":"publisher","first-page":"4425","DOI":"10.1042\/BCJ20200656","article-title":"Biochemical\nand transcript level differences between the three human phosphofructokinases\nshow optimization of each isoform for specific metabolic niches","volume":"477","author":"Fernandes","year":"2020","journal-title":"Biochem. J."},{"key":"2026090312084251100_cit7","doi-asserted-by":"publisher","first-page":"5644","DOI":"10.1016\/S0021-9258(17)33106-X","article-title":"Phosphofructokinase. III. Correlation\nof the regulatory kinetic and molecular properties of the rabbit muscle\nenzyme","volume":"251","author":"Frieden","year":"1976","journal-title":"J. Biol. Chem."},{"key":"2026090312084251100_cit8","doi-asserted-by":"publisher","first-page":"5630","DOI":"10.1016\/S0021-9258(17)33104-6","article-title":"Phosphofructokinase.\nI. Mechanism of the pH-dependent\ninactivation and reactivation of the rabbit muscle enzyme","volume":"251","author":"Bock","year":"1976","journal-title":"J. Biol. Chem."},{"key":"2026090312084251100_cit9","doi-asserted-by":"publisher","first-page":"5637","DOI":"10.1016\/S0021-9258(17)33105-8","article-title":"Phosphofructokinase. II. Role of\nligands in pH-dependent\nstructural changes of the rabbit muscle enzyme","volume":"251","author":"Bock","year":"1976","journal-title":"J. Biol. Chem."},{"key":"2026090312084251100_cit10","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1515\/hsz-2013-0130","article-title":"Structure and allosteric regulation\nof eukaryotic 6-phosphofructokinases","volume":"394","author":"Scho\u0308neberg","year":"2013","journal-title":"Bchm"},{"key":"2026090312084251100_cit11","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/S0022-2836(65)80285-6","article-title":"On the\nnature of allosteric transitions:\nA plausible model","volume":"12","author":"Monod","year":"1965","journal-title":"J. Mol. Biol."},{"key":"2026090312084251100_cit12","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1038\/326811a0","article-title":"Conversion of allosteric inhibition to activation in\nphosphofructokinase by protein engineering","volume":"326","author":"Tat-Kwong Lau","year":"1987","journal-title":"Nature"},{"key":"2026090312084251100_cit13","doi-asserted-by":"publisher","first-page":"6841","DOI":"10.1021\/bi00443a010","article-title":"Dissection\nof the effector-binding site and complementation\nstudies of Escherichia coli phosphofructokinase\nusing site-directed mutagenesis","volume":"28","author":"Lau","year":"1989","journal-title":"Biochemistry"},{"key":"2026090312084251100_cit14","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1016\/0022-2836(89)90246-5","article-title":"Crystal structure\nof unliganded phosphofructokinase\nfrom Escherichia coli","volume":"207","author":"Rypniewski","year":"1989","journal-title":"J. Mol. 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Biol."},{"key":"2026090312084251100_cit17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1000293","article-title":"Allosteric Communication Occurs via\nNetworks of Tertiary\nand Quaternary Motions in Proteins","volume":"5","author":"Daily","year":"2009","journal-title":"PLoS Comput.\nBiol."},{"key":"2026090312084251100_cit18","doi-asserted-by":"publisher","first-page":"1833","DOI":"10.1016\/j.bpj.2020.09.019","article-title":"Synergistic\nallostery in multiligand-protein\ninteractions","volume":"119","author":"Ghode","year":"2020","journal-title":"Biophys. 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Commun."},{"key":"2026090312084251100_cit30","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1038\/nature13001","article-title":"The ensemble nature\nof allostery","volume":"508","author":"Motlagh","year":"2014","journal-title":"Nature"},{"key":"2026090312084251100_cit31","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1038\/nature06522","article-title":"Dynamic personalities\nof proteins","volume":"450","author":"Henzler-Wildman","year":"2007","journal-title":"Nature"},{"key":"2026090312084251100_cit32","doi-asserted-by":"publisher","first-page":"6656","DOI":"10.1021\/bi00269a007","article-title":"A proteolyzed derivative of E. coli phosphofructokinase is no longer sensitive to allosteric effectors\nand still shows cooperativity in substrate binding","volume":"21","author":"Le Bras","year":"1982","journal-title":"Biochemistry"},{"key":"2026090312084251100_cit33","doi-asserted-by":"publisher","first-page":"4252","DOI":"10.1021\/acs.biochem.8b00028","article-title":"Structural\nInsights into the Regulation of Staphylococcus aureus Phosphofructokinase by Tetramer\u2013Dimer Conversion","volume":"57","author":"Tian","year":"2018","journal-title":"Biochemistry"},{"key":"2026090312084251100_cit34","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1021\/bi401402j","article-title":"Allosteric Regulation\nin Phosphofructokinase\nfrom the Extreme Thermophile Thermus thermophilus","volume":"53","author":"McGresham","year":"2014","journal-title":"Biochemistry"},{"key":"2026090312084251100_cit35","doi-asserted-by":"publisher","first-page":"9237","DOI":"10.1021\/bi00153a017","article-title":"Site-directed mutagenesis\nidentifies catalytic residues\nin the active site of Escherichia coli phosphofructokinase","volume":"31","author":"Berger","year":"1992","journal-title":"Biochemistry"},{"key":"2026090312084251100_cit36","doi-asserted-by":"publisher","first-page":"56037","DOI":"10.1371\/journal.pone.0056037","article-title":"Characterization\nof Phosphofructokinase Activity in Mycobacterium tuberculosis Reveals\nThat a Functional Glycolytic Carbon Flow Is Necessary to Limit the\nAccumulation of Toxic Metabolic Intermediates under Hypoxia","volume":"8","author":"Phong","year":"2013","journal-title":"PLoS One"},{"key":"2026090312084251100_cit37","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.1039\/C0CS00113A","article-title":"Hydrogen\nexchange mass spectrometry for studying protein\nstructure and dynamics","volume":"40","author":"Konermann","year":"2011","journal-title":"Chem. Soc. Rev."},{"key":"2026090312084251100_cit38","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1038\/s41589-025-02049-1","article-title":"Site-resolved\nenergetic information from HX\u2013MS experiments","volume":"22","author":"Lu","year":"2026","journal-title":"Nat. Chem. Biol."},{"key":"2026090312084251100_cit39","doi-asserted-by":"publisher","first-page":"1496","DOI":"10.1038\/s41557-026-02163-0","article-title":"Distinct energetic\nblueprints diversify\nfunction of conserved protein folds","volume":"18","author":"Wells","year":"2025","journal-title":"Nat. Chem."},{"key":"2026090312084251100_cit40","first-page":"683809","article-title":"A machine\nlearning method for calculating highly localized protein stabilities","author":"Lu","year":"2025","journal-title":"Nat. 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Commun."},{"key":"2026090312084251100_cit54","first-page":"41","article-title":"Anton 2: Raising the Bar for Performance and Programmability in a\nSpecial-Purpose Molecular Dynamics Supercomputer","volume-title":"SC\u201914: Proceedings of the International Conference\nfor High Performance Computing, Networking, Storage and Analysis","author":"Shaw","year":"2014"},{"key":"2026090312084251100_cit55","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1038\/s41592-022-01585-1","article-title":"US-align: universal\nstructure alignments of proteins, nucleic acids, and macromolecular\ncomplexes","volume":"19","author":"Zhang","year":"2022","journal-title":"Nat. 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