Journal article
Allosteric effects of the antipsychotic drug trifluoperazine on the energetics of calcium binding by calmodulin
Proteins, structure, function, and bioinformatics, Vol.78(10), pp.2265-2282
08/01/2010
DOI: 10.1002/prot.22739
PMCID: PMC2913171
PMID: 20544963
Abstract
Trifluoperazine (TFP; Stelazine™) is an antagonist of calmodulin (CaM), an essential regulator of calcium‐dependent signal transduction. Reports differ regarding whether, or where, TFP binds to apo CaM. Three crystallographic structures (1CTR, 1A29, and 1LIN) show TFP bound to (Ca2+)4‐CaM in ratios of 1, 2, or 4 TFP per CaM. In all of these, CaM domains adopt the “open” conformation seen in CaM‐kinase complexes having increased calcium affinity. Most reports suggest TFP also increases calcium affinity of CaM. To compare TFP binding to apo CaM and (Ca2+)4‐CaM and explore differential effects on the N‐ and C‐domains of CaM, stoichiometric TFP titrations of CaM were monitored by 15N‐HSQC NMR. Two TFP bound to apo CaM, whereas four bound to (Ca2+)4‐CaM. In both cases, the preferred site was in the C‐domain. During the titrations, biphasic responses for some resonances suggested intersite interactions. TFP‐binding sites in apo CaM appeared distinct from those in (Ca2+)4‐CaM. 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‐motifs on CaM. However, at the highest level tested, TFP raised the calcium affinity of the N‐domain 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 “closed,” “semi‐open,” and “open” domains of CaM. In physiological processes, apo CaM, as well as (Ca2+)4‐CaM, needs to be considered a potential target of drug action. Proteins 2010. © 2010 Wiley‐Liss, Inc.
Details
- Title: Subtitle
- Allosteric effects of the antipsychotic drug trifluoperazine on the energetics of calcium binding by calmodulin
- Creators
- Michael D FeldkampSusan E O'DonnellLiping YuMadeline A Shea
- Resource Type
- Journal article
- Publication Details
- Proteins, structure, function, and bioinformatics, Vol.78(10), pp.2265-2282
- DOI
- 10.1002/prot.22739
- PMID
- 20544963
- PMCID
- PMC2913171
- NLM abbreviation
- Proteins
- ISSN
- 0887-3585
- eISSN
- 1097-0134
- Publisher
- Wiley Subscription Services, Inc., A Wiley Company; Hoboken
- Number of pages
- 18
- Grant note
- Roy J. Carver Charitable Trust (01‐224) National Institutes of Health (RO1 GM 57001) University of Iowa Center for Biocatalysis and Bioprocessing Fellowship American Heart Association Predoctoral Fellowship
- Language
- English
- Date published
- 08/01/2010
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology; Medicine Administration
- Record Identifier
- 9984025266302771
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