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High\u2010affinity CBG (haCBG) undergoes proteolysis of the reactive center loop (RCL) by neutrophil elastase (NE) altering conformation to low\u2010affinity CBG (laCBG). Elevated temperature reduces CBG:cortisol binding affinity. Surface plasmon resonance was used to determine binding profiles of 19 steroids to haCBG and laCBG at 25, 37, and 39\u00b0C mimicking pyrexia and pH 7.4 and 7.0 mimicking acidosis, pathophysiological conditions relevant to sepsis. An expected 4\u20138\u2010fold reduction in affinity for cortisol, cortisone, corticosterone, 11\u2010deoxycortisol, progesterone, 17\u2010hydroxyprogesterone, and prednisolone occurred with NE\u2010mediated haCBG\u2010to\u2010laCBG conversion. CBG:cortisol binding affinity was further reduced 3.5\u2010fold at 39\u00b0C relative to 37\u00b0C, binding affinity was also reduced by acidosis for both haCBG and laCBG. Using a conformational antibody generated against the RCL, we confirmed RCL antibody binding was eliminated by NE cleavage, but preserved in pyrexia and acidosis. Molecular modeling studies performed at 40\u00b0C confirmed a critical role for Trp371, positioned within the steroid\u2010binding pocket, in ligand binding. These studies demonstrated CBG binding affinity to range of steroids is ligand specific and is reduced with NE\u2010mediated haCBG\u2010to\u2010laCBG transition. Reduced CBG:cortisol binding occurs with increased temperature and in acidosis. Increased flexibility of the Trp371 side chain is proposed in the thermo\u2010coupling mechanism of cortisol release. The synergy of NE cleavage, pyrexia, and acidosis on CBG:cortisol binding may serve to enhance cortisol delivery to the interstitial space in inflammation.<\/jats:p>","DOI":"10.1002\/pro.3982","type":"journal-article","created":{"date-parts":[[2020,10,21]],"date-time":"2020-10-21T14:01:21Z","timestamp":1603288881000},"page":"2495-2509","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Pyrexia and acidosis act independently of neutrophil elastase reactive center loop cleavage to effect cortisol release from corticosteroid\u2010binding globulin"],"prefix":"10.1002","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7450-5808","authenticated-orcid":false,"given":"Emily J.","family":"Meyer","sequence":"first","affiliation":[{"name":"Endocrine and Metabolic Unit Royal Adelaide Hospital  Adelaide South Australia Australia"},{"name":"Discipline of Medicine University of Adelaide  Adelaide South Australia Australia"},{"name":"Department of Endocrinology and Diabetes The Queen Elizabeth Hospital  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Torpy","sequence":"additional","affiliation":[{"name":"Endocrine and Metabolic Unit Royal Adelaide Hospital  Adelaide South Australia Australia"},{"name":"Discipline of Medicine University of Adelaide  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Chernykh","sequence":"additional","affiliation":[{"name":"Department of Molecular Sciences Macquarie University  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten","family":"Thaysen\u2010Andersen","sequence":"additional","affiliation":[{"name":"Department of Molecular Sciences Macquarie University  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marni A.","family":"Nenke","sequence":"additional","affiliation":[{"name":"Endocrine and Metabolic Unit Royal Adelaide Hospital  Adelaide South Australia Australia"},{"name":"Discipline of Medicine University of Adelaide  Adelaide South Australia Australia"},{"name":"Department of Endocrinology and Diabetes The Queen Elizabeth Hospital  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John G.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Steroid &amp; Immunobiochemistry Laboratory Canterbury Health Laboratories  Christchurch New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harinda","family":"Rajapaksha","sequence":"additional","affiliation":[{"name":"Department of Biochemistry &amp; Genetics, La Trobe Institute for Molecular Science La Trobe University  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne","family":"Rankin","sequence":"additional","affiliation":[{"name":"Endocrine and Metabolic Unit Royal Adelaide Hospital  Adelaide South Australia Australia"},{"name":"Discipline of Medicine University of Adelaide  Adelaide South Australia Australia"},{"name":"Chemical Pathology Directorate, SA Pathology  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven W.","family":"Polyak","sequence":"additional","affiliation":[{"name":"Clinical and Health Sciences University of South Australia  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,11,4]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"3136","article-title":"Corticosteroid\u2010binding globulin. 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