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The two activities require different conformations of APE1. As an endonuclease, APE1 is fully folded. As a redox factor, APE1 must be partially unfolded to expose the buried residue Cys65, which reduces transcription factors including AP\u20101, NF\u2010\u03baB, and HIF\u20101\u03b1 and thereby enables them to bind DNA. To determine a molecular basis for partial unfolding associated with APE1's redox activity, we characterized specific interactions of a known redox inhibitor APX3330 with APE1 through waterLOGSY and\n                    <jats:sup>1<\/jats:sup>\n                    H\u2013\n                    <jats:sup>15<\/jats:sup>\n                    N HSQC NMR approaches using ethanol and acetonitrile as co\u2010solvents. We find that APX3330 binds to the endonuclease active site in both co\u2010solvents and to a distant small pocket in acetonitrile. Prolonged exposure of APE1 with APX3330 in acetonitrile resulted in a time\u2010dependent loss of\n                    <jats:sup>1<\/jats:sup>\n                    H\u2013\n                    <jats:sup>15<\/jats:sup>\n                    N HSQC chemical shifts (~35%), consistent with partial unfolding. Regions that are partially unfolded include adjacent N\u2010 and C\u2010terminal beta strands within one of the two sheets comprising the core, which converge within the small binding pocket defined by the CSPs. Removal of APX3330 via dialysis resulted in a slow reappearance of the\n                    <jats:sup>1<\/jats:sup>\n                    H\u2013\n                    <jats:sup>15<\/jats:sup>\n                    N HSQC chemical shifts suggesting that the effect of APX3330 is reversible. APX3330 significantly decreases the melting temperature of APE1 but has no effect on endonuclease activity using a standard assay in either co\u2010solvent. Our results provide insights on reversible partial unfolding of APE1 relevant for its redox function as well as the mechanism of redox inhibition by APX3330.\n                  <\/jats:p>","DOI":"10.1002\/pro.70148","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T06:54:55Z","timestamp":1747292095000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Chemically induced partial unfolding of the multifunctional apurinic\/apyrimidinic endonuclease 1"],"prefix":"10.1002","volume":"34","author":[{"given":"Ratan","family":"Rai","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olabode I.","family":"Dawodu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Indiana 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