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Three crystallographic structures (1CTR, 1A29, and 1LIN) show TFP bound to (Ca<jats:sup>2+<\/jats:sup>)<jats:sub>4<\/jats:sub>\u2010CaM in ratios of 1, 2, or 4 TFP per CaM. In all of these, CaM domains adopt the \u201copen\u201d conformation seen in CaM\u2010kinase complexes having increased calcium affinity. Most reports suggest TFP also increases calcium affinity of CaM. To compare TFP binding to apo CaM and (Ca<jats:sup>2+<\/jats:sup>)<jats:sub>4<\/jats:sub>\u2010CaM and explore differential effects on the N\u2010 and C\u2010domains of CaM, stoichiometric TFP titrations of CaM were monitored by<jats:sup>15<\/jats:sup>N\u2010HSQC NMR. Two TFP bound to apo CaM, whereas four bound to (Ca<jats:sup>2+<\/jats:sup>)<jats:sub>4<\/jats:sub>\u2010CaM. In both cases, the preferred site was in the C\u2010domain. During the titrations, biphasic responses for some resonances suggested intersite interactions. TFP\u2010binding sites in apo CaM appeared distinct from those in (Ca<jats:sup>2+<\/jats:sup>)<jats:sub>4<\/jats:sub>\u2010CaM. In equilibrium calcium titrations at defined ratios of TFP:CaM, TFP reduced calcium affinity at most levels tested; this is similar to the effect of many IQ\u2010motifs on CaM. However, at the highest level tested, TFP raised the calcium affinity of the N\u2010domain of CaM. A model of conformational switching is proposed to explain how TFP can exert opposing allosteric effects on calcium affinity by binding to different sites in the \u201cclosed,\u201d \u201csemi\u2010open,\u201d and \u201copen\u201d domains of CaM. In physiological processes, apo CaM, as well as (Ca<jats:sup>2+<\/jats:sup>)<jats:sub>4<\/jats:sub>\u2010CaM, needs to be considered a potential target of drug action. Proteins 2010. \u00a9 2010 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/prot.22739","type":"journal-article","created":{"date-parts":[[2010,4,5]],"date-time":"2010-04-05T19:09:38Z","timestamp":1270494578000},"page":"2265-2282","source":"Crossref","is-referenced-by-count":26,"title":["Allosteric effects of the antipsychotic drug trifluoperazine on the energetics of calcium binding by calmodulin"],"prefix":"10.1002","volume":"78","author":[{"given":"Michael D.","family":"Feldkamp","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan E.","family":"O'Donnell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline 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